Gyrase inhibitors and uses thereof

ABSTRACT

The present invention relates to compounds which inhibit bacterial gyrase and/or Topo IV and pharmaceutically acceptable compositions comprising said compounds. These compounds, and compositions thereof, are useful in treating bacterial infection. Accordingly, the present invention also relates to methods for treating bacterial infections in mammals.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional PatentApplication 60/443,917 filed Jan. 31, 2003, the contents of which areincorporated herein by reference.

FIELD OF THE INVENTION

[0002] This invention is in the field of medicinal chemistry and relatesto compounds, and pharmaceutical compositions thereof, that inhibitbacterial gyrase and Topo IV. The compounds are useful as inhibitors ofbacterial gyrase and Topo IV activity. The present invention alsorelates to methods for treating bacterial infections in mammals and tomethods for decreasing bacterial quantity in a biological sample.

BACKGROUND OF THE INVENTION

[0003] Bacterial resistance to antibiotics has long been recognized, andit is today considered to be a serious worldwide health problem. As aresult of resistance, some bacterial infections are either difficult totreat with antibiotics or even untreatable. This problem has becomeespecially serious with the recent development of multiple drugresistance in certain strains of bacteria, such as Streptococcuspneumoniae (SP), Mycobacterium tuberculosis, and Enterococcus. Theappearance of vancomycin resistant enterococcus was particularlyalarming because vancomycin was formerly the only effective antibioticfor treating this infection, and had been considered for many infectionsto be the drug of “last resort”. While many other drug-resistantbacteria do not cause life-threatening disease, such as enterococci,there is the fear that the genes which induce resistance might spread tomore deadly organisms such as Staphylococcus aureus, where methicillinresistance is already prevalent (De Clerq, et al., Current Opinion inAnti-infective Investigational Drugs, 1999, 1, 1; Levy, “The Challengeof Antibiotic Resistance”, Scientific American, March, 1998).

[0004] Another concern is how quickly antibiotic resistance can spread.For example, until the 1960's SP was universally sensitive topenicillin, and in 1987 only 0.02% of the SP strains in the U.S. wereresistant. However, by 1995 it was reported that SP resistance topenicillin was about seven percent and as high as 30% in some parts ofthe U.S. (Lewis, FDA Consumer magazine (September, 1995); Gershman inThe Medical Reporter, 1997).

[0005] Hospitals, in particular, serve as centers for the formation andtransmission of drug-resistant organisms. Infections occurring inhospitals, known as nosocomial infections, are becoming an increasinglyserious problem. Of the two million Americans infected in hospitals eachyear, more than half of these infections resist at least one antibiotic.The Center for Disease Control reported that in 1992, over 13,000hospital patients died of bacterial infections that were resistant toantibiotic treatment (Lewis, “The Rise of Antibiotic-ResistantInfections”, FDA Consumer magazine, September, 1995).

[0006] As a result of the need to combat drug-resistant bacteria and theincreasing failure of the available drugs, there has been a resurgentinterest in discovering new antibiotics. One attractive strategy fordeveloping new antibiotics is to inhibit DNA gyrase, a bacterial enzymenecessary for DNA replication, and therefore, necessary for bacterialcell growth and division. Gyrase activity is also associated with eventsin DNA transcription, repair and recombination.

[0007] Gyrase is one of the topoisomerases, a group of enzymes whichcatalyze the interconversion of topological isomers of DNA (seegenerally, Kornberg and Baker, DNA Replication, 2d Ed., Chapter 12,1992, W. H. Freeman and Co.; Drlica, Molecular Microbiology, 1992, 6,425; Drlica and Zhao, Microbiology and Molecular Biology Reviews, 1997,61, 377). Gyrase itself controls DNA supercoiling and relievestopological stress that occurs when the DNA strands of a parental duplexare untwisted during the replication process. Gyrase also catalyzes theconversion of relaxed, closed circular duplex DNA to a negativelysuperhelical form which is more favorable for recombination. Themechanism of the supercoiling reaction involves the wrapping of gyrasearound a region of the DNA, double strand breaking in that region,passing a second region of the DNA through the break, and rejoining thebroken strands. Such a cleavage mechanism is characteristic of a type IItopoisomerase. The supercoiling reaction is driven by the binding of ATPto gyrase. The ATP is then hydrolyzed during the reaction. This ATPbinding and subsequent hydrolysis cause conformational changes in theDNA-bound gyrase that are necessary for its activity. It has also beenfound that the level of DNA supercoiling (or relaxation) is dependent onthe ATP/ADP ratio. In the absence of ATP, gyrase is only capable ofrelaxing supercoiled DNA.

[0008] Bacterial DNA gyrase is a 400 kilodalton protein tetramerconsisting of two A (GyrA) and two B subunits (GyrB). Binding andcleavage of the DNA is associated with GyrA, whereas ATP is bound andhydrolyzed by the GyrB protein. GyrB consists of an amino-terminaldomain which has the ATPase activity, and a carboxy-terminal domainwhich interacts with GyrA and DNA. By contrast, eukaryotic type IItopoisomerases are homodimers that can relax negative and positivesupercoils, but cannot introduce negative supercoils. Ideally, anantibiotic based on the inhibition of bacterial DNA gyrase would beselective for this enzyme and be relatively inactive against theeukaryotic type II topoisomerases.

[0009] The widely used quinolone antibiotics inhibit bacterial DNAgyrase. Examples of the quinolones include the early compounds such asnalidixic acid and oxolinic acid, as well as the later, more potentfluoroquinolones such as norfloxacin, ciprofloxacin, and trovafloxacin.These compounds bind to GyrA and stabilize the cleaved complex, thusinhibiting overall gyrase function, leading to cell death. However, drugresistance has also been recognized as a problem for this class ofcompounds (WHO Report, “Use of Quinolones in Food Animals and PotentialImpact on Human Health”, 1998). With the quinolones, as with otherclasses of antibiotics, bacteria exposed to earlier compounds oftenquickly develop cross-resistance to more potent compounds in the sameclass.

[0010] There are fewer known inhibitors that bind to GyrB. Examplesinclude the coumarins, novobiocin and coumermycin A1, cyclothialidine,cinodine, and clerocidin. The coumarins have been shown to bind to GyrBvery tightly. For example, novobiocin makes a network of hydrogen bondswith the protein and several hydrophobic contacts. While novobiocin andATP do appear to bind within the ATP binding site, there is minimaloverlap in the bound orientation of the two compounds. The overlappingportions are the sugar unit of novobiocin and the ATP adenine (Maxwell,Trends in Microbiology, 1997, 5, 102).

[0011] For coumarin-resistant bacteria, the most prevalent pointmutation is at a surface arginine residue that binds to the carbonyl ofthe coumarin ring (Arg136 in E. coli GyrB). While enzymes with thismutation show lower supercoiling and ATPase activity, they are also lesssensitive to inhibition by coumarin drugs (Maxwell, Mol. Microbiol.,1993, 9, 681).

[0012] Despite being potent inhibitors of gyrase supercoiling, thecoumarins have not been widely used as antibiotics. They are generallynot suitable due to their low permeability in bacteria, eukaryotictoxicity, and poor water solubility (Maxwell, Trends in Microbiology,1997, 5, 102). It would be desirable to have a new, effective GyrBinhibitor that overcomes these drawbacks. Such an inhibitor would be anattractive antibiotic candidate, without a history of resistanceproblems that plague other classes of antibiotics.

[0013] Replication fork movement along circular DNA can generatetopological changes both ahead of the replication complex as well asbehind in the already replicated regions (Champoux, J. J., Annu. Rev.Biochem., 2001, 70, 369-413). While DNA gyrase can introduce negativesupercoils to compensate for the topological stresses ahead of thereplication fork, some overwinding can diffuse back into the alreadyreplicated region of DNA resulting in precatenanes. If not removed, thepresence of the precatenanes can result in interlinked (catenated)daughter molecules at the end of replication. TopoIV is responsible forseparating the catenated daughter plasmids as well as removal ofprecatenanes formed during replication ultimately allowing forsegragation of the daughter molecules into daughter cells. Topo IV iscomposed of two ParC and 2 parE subunits as a C2E2 tetramer (where the Cand E monomers are homologuous to the A and B monomers of gyrase,respectively) that requires ATP hydrolysis (at the N-terminus of the Esubunit) to reset the enzyme to re-enter the catalytic cycle. Topo IV ishighly conserved among bacteria and is essential for bacterialreplication (Drlica and Zhao, Microbiol. Mol. Biol. Rev., 1997, 61,377).

[0014] While little attention has been paid to inhibitors that targetParE of TopoIV, the action of the newer quinolones on the ParC regionhas been widely studied (Hooper, D. C., Clin. Infect. Dis., 2000,31(Suppl 2): S24-28). It has been demonstrated that moxifloxacin andgatifloxacin have more balanced activities against Gyrase and TopoIVresulting in expanded Gram positive coverage as well as lower levels ofresistance caused primary-target mutation. In those cases,susceptibility is limited by the sensitivity of the second target to theantibacterial agent. Thus, agents that can effectively inhibit multipleessential targets can result in an expanded spectrum of potencies,improved antibacterial potencies, improved potency against single targetmutants, and/or lower spontaneous rates of resistance.

[0015] As bacterial resistance to antibiotics has become an importantpublic health problem, there is a continuing need to develop newer andmore potent antibiotics. More particularly, there is a need forantibiotics that represent a new class of compounds not previously usedto treat bacterial infection. Such compounds would be particularlyuseful in treating nosocomial infections in hospitals where theformation and transmission of resistant bacteria are becomingincreasingly prevalent.

SUMMARY OF THE INVENTION

[0016] It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are effective asinhibitors of gyrase and/or Topo IV. These compounds have the generalformula I:

[0017] or a pharmaceutically acceptable salt thereof, wherein R¹, R², W,X, Z, and Ring A are as defined below.

[0018] These compounds, and pharmaceutically acceptable compositionsthereof, are useful for treating or lessening the severity of bacterialinfections. In particular, the compounds of the present invention areuseful in treating or lessening the severity of urinary tractinfections, pneumonia, prostatitis, skin and soft tissue infections,intra-abdominal infections, blood stream infections, or infections offebrile neutropenic patients

DESCRIPTION OF THE INVENTION

[0019] The present invention relates to a compound of formula I:

[0020] or a pharmaceutically acceptable salt thereof, wherein:

[0021] W is selected from nitrogen, CH, or CF;

[0022] X is selected from CH or CF;

[0023] Z is O or NH;

[0024] R′ is phenyl or a 5-6 membered heteroaryl ring having 1-3heteroatoms independently selected from oxygen, nitrogen, or sulfur,wherein:

[0025] R¹ is substituted with 0-3 groups independently selected from-(T)_(y)-Ar, R′, oxo, C(O)R′, CO₂R′, OR′, N(R′)₂, SR′, NO₂, halogen, CN,C(O)N(R′)₂, NR′C(O)R′, SO₂R′, SO₂N(R′)₂, or NR′SO₂R′;

[0026] y is 0 or 1;

[0027] T is a straight or branched C₁₋₄ alkylidene chain, wherein onemethylene unit of T is optionally replaced by —O—, —NH—, or —S—;

[0028] each R′ is independently selected from hydrogen, C₁₋₄ aliphatic,or a 5-6 membered saturated, unsaturated, or aryl ring having 0-3heteroatoms independently selected from nitrogen, oxygen, or sulfur,wherein:

[0029] R′ is substituted with 0-3 groups independently selected fromhalogen, oxo, R^(o), N(R^(o))₂, OR^(o), CO₂R^(o), NR^(o)C(O)R^(o),C(O)N(R^(o))₂, SO₂R^(o), SO₂N(R^(o))₂, or NR^(o)SO₂R^(o), wherein:

[0030] each R^(o) is independently selected from hydrogen, C₁₋₄aliphatic, or a 5-6 membered saturated, unsaturated, or aryl ring having0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur,and wherein:

[0031] two substituents on adjacent positions of R¹ may be takentogether to form a 5-7 membered saturated, partially unsaturated, oraryl ring having 0-3 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

[0032] Ar is a 3-8 membered saturated, unsaturated, or aryl ring, a 3-7membered heterocyclic ring having 1-3 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, or a 5-6 membered heteroaryl ringhaving 1-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, wherein:

[0033] Ar is substituted with 0-3 groups independently selected from R′,oxo, CO₂R′, OR′, N(R′)₂, SR′, NO₂, halogen, CN, C(O)N(R′)₂, NR′C(O)R′,SO₂R′, C(O)R′, SO₂N(R′)₂, or NR′SO₂R′;

[0034] R² is selected from hydrogen or a C₁₋₃ aliphatic group; and

[0035] Ring A is a 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, provided thatsaid ring has a hydrogen-bond acceptor in the position adjacent to thepoint of attachment to Ring B, wherein:

[0036] Ring A is substituted with 0-3 groups independently selected fromR′, oxo, CO₂R′, OR′, N(R′)₂, SR′, NO₂, halogen, CN, C(O)N(R′)₂,NR′C(O)R′, SO₂R′, SO₂N(R′)₂, or NR′SO₂R′, and wherein:

[0037] two substituents on adjacent positions of Ring A may be takentogether to form a 5-7 membered saturated, partially unsaturated, oraryl ring having 0-3 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

[0038] As used herein, the following definitions shall apply unlessotherwise indicated.

[0039] The phrase “optionally substituted” is used interchangeably withthe phrase “substituted or unsubstituted.” Unless otherwise indicated,an optionally substituted group may have a substituent at eachsubstitutable position of the group, and each substitution isindependent of the other.

[0040] The term “aliphatic” or “aliphatic group”, as used herein, meansa straight-chain or branched C₁-C₈ hydrocarbon chain that is completelysaturated or that contains one or more units of unsaturation, or amonocyclic C₃-C₈ hydrocarbon or bicyclic C₈-C₁₂ hydrocarbon that iscompletely saturated or that contains one or more units of unsaturation,but which is not aromatic (also referred to herein as “carbocycle” or“cycloalkyl”), that has a single point of attachment to the rest of themolecule wherein any individual ring in said bicyclic ring system has3-7 members. For example, suitable aliphatic groups include, but are notlimited to, linear or branched or alkyl, alkenyl, alkynyl groups andhybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

[0041] The terms “alkyl”, “alkoxy”, “hydroxyalkyl”, “alkoxyalkyl”, and“alkoxycarbonyl”, used alone or as part of a larger moiety include bothstraight and branched chains containing one to twelve carbon atoms. Theterms “alkenyl” and “alkynyl” used alone or as part of a larger moietyshall include both straight and branched chains containing two to twelvecarbon atoms.

[0042] The term “heteroatom” means nitrogen, oxygen, or sulfur andincludes any oxidized form of nitrogen and sulfur, and the quatemizedform of any basic nitrogen. Also the term “nitrogen” includes asubstitutable nitrogen of a heterocyclic ring. As an example, in asaturated or partially unsaturated ring having 0-3 heteroatoms selectedfrom oxygen, sulfur or nitrogen, the nitrogen may be N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl).

[0043] The term “unsaturated”, as used herein, means that a moiety hasone or more units of unsaturation, and includes aryl rings.

[0044] The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic, bicyclicand tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic and whereineach ring in the system contains 3 to 7 ring members. The term “aryl”may be used interchangeably with the term “aryl ring”. The term “aryl”also refers to heteroaryl ring systems as defined hereinbelow.

[0045] The term “heterocycle”, “heterocyclyl”, or “heterocyclic” as usedherein means non-aromatic, monocyclic, bicyclic or tricyclic ringsystems having five to fourteen ring members in which one or more ringmembers is a heteroatom, wherein each ring in the system contains 3 to 7ring members.

[0046] The term “heteroaryl”, used alone or as part of a larger moietyas in “heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic,bicyclic and tricyclic ring systems having a total of five to fourteenring members, wherein at least one ring in the system is aromatic, atleast one ring in the system contains one or more heteroatoms, andwherein each ring in the system contains 3 to 7 ring members. The term“heteroaryl” may be used interchangeably with the term “heteroaryl ring”or the term “heteroaromatic”.

[0047] The term “hydrogen bond acceptor”, as used herein, means an atomcapable of accepting a hydrogen bond. A typical hydrogen bond acceptoris a sulfur, oxygen, or nitrogen atom, especially a nitrogen that issp²-hybridized, an ether oxygen, or a thioether sulfur. A preferredhydrogen bond acceptor is a nitrogen that is sp²-hybridized.

[0048] A combination of substituents or variables is permissible only ifsuch a combination results in a stable or chemically feasible compound.A stable compound or chemically feasible compound is one that is notsubstantially altered when kept at a temperature of 40° C. or less, inthe absence of moisture or other chemically reactive conditions, for atleast a week.

[0049] It will be apparent to one skilled in the art that certaincompounds of this invention may exist in tautomeric forms, all suchtautomeric forms of the compounds being within the scope of theinvention.

[0050] Unless otherwise stated, structures depicted herein are alsomeant to include all stereochemical forms of the structure; i.e., the Rand S configurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.Unless otherwise stated, structures depicted herein are also meant toinclude compounds that differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by a ¹³C— or ¹⁴C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools or probes in biological assays.

[0051] Examples of suitable Ring A moieties are set forth in Table 1below. TABLE 1

a

b

c

d

e

f

g

h

i

j

k

l

m

n

o

p

q

r

s

t

u

v

w

x

y

z

aa

bb

cc

dd

ee

ff

gg

hh

[0052] wherein each Ring A is optionally substituted as defined above.

[0053] According to one embodiment, Ring A of formula I is a 5-memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, provided that said ring has a hydrogen-bondacceptor in the position adjacent to the point of attachment to Ring B,wherein said Ring A is optionally substituted as defined herein supra.

[0054] According to another embodiment, Ring A of formula I is a6-membered heteroaryl ring having 1-3 nitrogens, provided that said ringhas a nitrogen atom in the position adjacent to the point of attachmentto Ring B, wherein said Ring A is optionally substituted as definedherein supra.

[0055] In certain embodiments, Ring A moieties of formula I are selectedfrom rings a, b, c, d, e, f, g, h, i, j, k, l, m, p, q, r, s, t, v, w,x, y, z, aa, bb, cc, dd, and ee, wherein each Ring A is optionallysubstituted as defined above.

[0056] In other embodiments, the Ring A moieties of formula I areselected from rings a, f, l, s, w, y, and z, wherein each Ring A isoptionally substituted as defined above.

[0057] When Ring A of formula I is a bicyclic heteroaryl ring, preferredbicyclic Ring A moieties include benzothiazole, benzimidazole,benzoxazole, and quinoline.

[0058] According to one embodiment, substituents on Ring A of formula I,if present, are selected from oxo, N(R′)₂, C(O)N(R′)₂, CO₂R′, halogen,N(R′)SO₂R′, C(O)R′, OR′, or R′. According to another embodiment, R′substituents on Ring A of formula I include methyl, ethyl, propyl,piperazinyl, piperidinyl, or morpholinyl, wherein said R′ groups areoptionally substituted with R^(o), N(R^(o))₂ or OR^(o).

[0059] According to one embodiment, the R¹ group of formula I isoptionally substituted phenyl.

[0060] According to another embodiment, the R¹ group of formula I is anoptionally substituted 5-membered heteroaryl ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

[0061] According to another embodiment, the R¹ group of formula I is anoptionally substituted 5-membered heteroaryl ring having 1-3 nitrogens.

[0062] Yet another embodiment of the present invention relates to acompound of formula I wherein R¹ is an optionally substituted 6-memberedheteroaryl ring having 1-2 nitrogens.

[0063] In certain embodiments, the R¹ group of formula I is selectedfrom an optionally substituted phenyl or 5-6 membered heteroaryl ringhaving 1-2 nitrogens. In other embodiments, the R¹ group of formula I isselected from an optionally substituted pyrid-2-yl, pyrid-3-yl,pyrid-4-yl, pyridone, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl,pyrimidin-6-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, orimidazol-5-yl ring. According to yet another embodiment, the R¹ group offormula I is an optionally substituted ring selected from pyrid-3-yl,pyrid-4-yl, pyridone, pyrimidin-5-yl, or imidazol-1-yl.

[0064] In certain embodiments, substituents on the R¹ group of formulaI, when present, are selected from halogen, oxo, -(T)_(y)-Ar, R′, CO₂R′,OR′, N(R′)₂, SR′, C(O)N(R′)₂, NR′C(O)R′, SO₂R′, SO₂N(R′)₂, or NR′SO₂R′.According to other embodiments, substituents on the R¹ group of formulaI, when present, are selected from oxo, fluoro, chloro, N(CH₃)₂,NHCH₂CH₃, NH-cyclopropyl, NH₂, NHC(O)CH₃, C(O)NHcyclopropyl, methyl,ethyl, t-butyl, isobutyl, cyclopropyl, isopropyl, CH₂phenyl,CH₂pyridin-3-yl, OH, OCH₃, OCH₂CH₃, OCH₂phenyl, OCH₂pyridin-3-yl,CH₂piperidinyl, CH₂cyclopropyl, or CH₂CH₂OCH₃.

[0065] According to one embodiment, R¹ is substituted with -(T)_(y)-Arwherein T is a straight or branched C₁₋₃ alkylidene chain wherein onemethylene unit of T is optionally replaced by —O—, —NH—, or —S—.According to another embodiment, T is a straight or branched C₁₋₃alkylidene chain wherein one methylene unit of T is replaced by —O—,—NH—, or —S—. Yet another embodiment of the present invention relates toa compound of formula I wherein R¹ is substituted with -(T)_(y)-Ar andAr is an optionally substituted 5-6 membered saturated ring having 1-2heteroatoms independently selected from oxygen, nitrogen, or sulfur.According to another embodiment, the Ar group of formula I is anoptionally substituted 5-membered heteroaryl ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. According toyet another embodiment, the Ar group of formula I is an optionallysubstituted 6-membered heteroaryl ring having 1-3 nitrogens. Yet anotherembodiment relates to a compound of formula I wherein Ar is optionallysubstituted phenyl.

[0066] When the R¹ group of formula I is substituted with -(T)_(y)-Ar,examples of substituents on Ar include halogen, OR′, R′, CO₂R′, SO₂R′,oxo, and C(O)R′.

[0067] According to one embodiment, when two substituents on adjacentpositions of R¹ of formula I are taken together to form an optionallysubstituted ring fused to R¹, rings formed thereby include 5-6 memberedsaturated, partially unsaturated, or aryl rings having 0-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. According toanother embodiment, said ring fused to R¹ is selected from a 5-memberedsaturated ring having two oxygens or a 6-membered saturated ring havingtwo oxygens. Examples of substituents on said ring fused to R¹ includehalogen, such as fluorine.

[0068] One embodiment of the present invention relates to a compound offormula I wherein R² is selected from methyl, ethyl, isopropyl, orcyclopropyl. According to another embodiment, R² is methyl or ethyl.According to yet another embodiment, R² of formula I is ethyl.

[0069] According to one embodiment, the present invention relates to acompound of formula I wherein Z is NH.

[0070] According to another embodiment, the present invention relates toa compound of formula I wherein Z is O.

[0071] Compounds of the present invention fall within the genus ofcompounds described in PCT/US 01/48855. However, applicants havediscovered that the presence of the Ring A moiety, as defined above,imparts surprising and unexpectedly increased gyrase inhibitory, TopoIVactivity, and antimicrobial potency.

[0072] According to one embodiment, the present invention relates to acompound of formula II:

[0073] or a pharmaceutically acceptable salt thereof, wherein Z, R² andRing A are as defined above and the imidazole ring depicted isoptionally substituted in the 4-position with C(O)N(R′)₂ and/orsubstituted in the 2-position with R′. Accordingly, another embodimentof the present invention relates to a compound of formula II-a:

[0074] or a pharmaceutically acceptable salt thereof, wherein Z, R², R′,and Ring A are as defined above.

[0075] Other embodiments describing R² and Ring A groups of formula II-aare those described for formula I above.

[0076] Other embodiments describing R′ groups of formula II-a areselected from hydrogen or C₁₋₄ aliphatic.

[0077] According to one embodiment, the present invention relates to acompound of formula II or II-a wherein Z is NH.

[0078] According to another embodiment, the present invention relates toa compound of formula II or II-a wherein Z is O.

[0079] According to another embodiment, the present invention relates toa compound of formula III:

[0080] or a pharmaceutically acceptable salt thereof, wherein Z, R² andRing A are as defined above, and the pyridone ring depicted issubstituted with 0-2 groups independently selected from —(CH₂)_(y)—Ar,halogen, oxo, R′, CO₂R′, OR′, N(R′)₂, SR′, C(O)N(R′)₂, NR′C(O)R′, SO₂R′,SO₂N(R′)₂, or NR′SO₂R′.

[0081] Other embodiments describing R² and Ring A groups of formula IIIare those described for formula I above.

[0082] Other embodiments describing substituents on the pyridone ring offormula III are those described above as preferred substituents on R¹ offormula I.

[0083] According to one embodiment, the present invention relates to acompound of formula III wherein Z is NH.

[0084] According to another embodiment, the present invention relates toa compound of formula III wherein Z is O.

[0085] According to another embodiment, the present invention relates toa compound of formula III-a:

[0086] or a pharmaceutically acceptable salt thereof, wherein Z, R′, R²and Ring A are as defined above.

[0087] Other embodiments describing R² groups of formula III-a are thosedescribed for R² groups of formula I above.

[0088] Other embodiments describing Ring A groups of formula III-a arethose described for Ring A groups of formula I above.

[0089] In certain embodiments, the R′ substituents on the pyridone ringof formula III-a are selected from hydrogen or C₁₋₄ aliphatic wherein R′is optionally substituted with phenyl or pyridyl. In other embodiments,the R′ substituents on the pyridone ring of formula III-a are selectedfrom methyl, ethyl, t-butyl, isobutyl, cyclopropyl, isopropyl,CH₂phenyl, CH₂pyridin-3-yl, CH₂piperidinyl, CH₂cyclopropyl, orCH₂CH₂OCH₃.

[0090] According to one embodiment, the present invention relates to acompound of formula III-a wherein Z is NH.

[0091] According to another embodiment, the present invention relates toa compound of formula III-a wherein Z is O.

[0092] Yet another embodiment of the present invention relates to acompound of formula IV:

[0093] or a pharmaceutically acceptable salt thereof, wherein y, Z, T,Ar, R² and Ring A are as defined above.

[0094] Other embodiments describing Ring A and R² groups of formula IVare those set forth for those Ring A and R² groups of formula I, supra.

[0095] According to one embodiment, the Ar group of formula IV is anoptionally substituted 5-6 membered saturated ring having 1-2heteroatoms independently selected from oxygen, nitrogen, or sulfur.

[0096] According to another embodiment, the Ar group of formula IV is anoptionally substituted 5-membered heteroaryl ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

[0097] According to another embodiment, the Ar group of formula IV is anoptionally substituted 6-membered heteroaryl ring having 1-3 nitrogens.

[0098] Yet another embodiment relates to a compound of formula IVwherein Ar is optionally substituted phenyl.

[0099] According to one embodiment, the present invention relates to acompound of formula IV wherein Z is NH.

[0100] Examples of substituents on the Ar group of formula IV includehalogen, OR′, R′, CO₂R′, SO₂R′, oxo, and C(O)R′.

[0101] According to another embodiment, the present invention relates toa compound of formula IV wherein Z is O.

[0102] Yet another embodiment of the present invention relates to acompound of formula V:

[0103] or a pharmaceutically acceptable salt thereof, wherein y, Z, R²and R′ are as defined above.

[0104] Other embodiments describing R¹ and R² groups of formula V arethose set forth for those R¹ and R² groups of formula I, supra.

[0105] According to one embodiment, the present invention relates to acompound of formula V wherein Z is NH.

[0106] Examples of substituents on the Ar group of formula IV includehalogen, OR′, R′, CO₂R′, SO₂R′, oxo, and C(O)R′.

[0107] According to another embodiment, the present invention relates toa compound of formula V wherein Z is O.

[0108] According to another embodiment of the present invention relatesto a compound of formula VI:

[0109] or a pharmaceutically acceptable salt thereof, wherein y, Z, T,Ar, and R² are as defined above.

[0110] Other embodiments describing the R² group of formula VI are thoseset forth for the R² group of formula I, supra.

[0111] According to one embodiment, the Ar group of formula VI is anoptionally substituted 5-6 membered saturated ring having 1-2heteroatoms independently selected from oxygen, nitrogen, or sulfur.

[0112] According to another embodiment, the Ar group of formula VI is anoptionally substituted 5-membered heteroaryl ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

[0113] According to another embodiment, the Ar group of formula VI is anoptionally substituted 6-membered heteroaryl ring having 1-3 nitrogens.

[0114] Yet another embodiment relates to a compound of formula VIwherein Ar is optionally substituted phenyl.

[0115] According to one embodiment, the present invention relates to acompound of formula VI wherein Z is NH.

[0116] Examples of substituents on the Ar group of formula VI includehalogen, OR′, R′, CO₂R′, SO₂R′, oxo, and C(O)R′.

[0117] According to another embodiment, the present invention relates toa compound of formula VI wherein Z is O.

[0118] Exemplary structures of formula I are set forth in Table 2 below.TABLE 2

I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-28

I-29

I-30

I-31

I-32

I-35

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

I-78

I-79

I-80

I-81

I-82

I-83

I-84

I-85

I-86

I-87

I-88

I-89

I-90

I-91

I-92

I-93

I-94

I-95

I-96

I-97

I-98

I-99

I-100

I-101

I-102

I-103

I-104

I-105

I-106

I-107

I-108

I-109

I-110

I-111

I-112

I-113

I-114

I-115

I-116

I-117

I-118

I-119

I-120

I-121

I-122

I-123

I-124

I-125

I-126

I-127

I-128

I-129

I-130

I-131

I-132

I-133

I-134

I-135

I-136

I-137

I-138

I-139

I-140

I-141

I-142

I-143

I-144

I-145

I-146

I-147

I-148

I-149

I-150

I-151

I-152

I-153

I-154

I-155

I-156

I-157

I-158

I-159

I-160

I-161

I-162

I-163

I-164

I-165

I-166

I-167

I-168

I-169

I-170

I-171

I-172

I-173

I-174

I-175

I-176

I-177

I-178

I-179

I-180

I-181

I-182

I-183

I-184

I-185

I-186

I-187

I-188

I-189

I-190

I-191

I-192

I-193

I-194

I-195

I-196

I-197

I-198

I-199

I-200

I-201

I-202

I-203

I-204

I-205

I-206

I-207

I-208

I-209

I-210

I-211

I-212

I-212

I-214

I-215

I-216

I-217

I-218

I-219

I-220

I-221

I-222

I-223

I-224

I-225

I-226

I-227

I-228

I-229

I-230

I-231

I-232

I-233

I-234

I-235

I-236

I-237

I-238

I-239

I-240

I-241

I-242

I-243

I-244

I-245

I-246

I-247

I-248

I-249

I-250

I-251

I-252

I-253

I-254

I-255

I-256

I-257

I-258

I-259

I-260

I-261

I-262

I-263

I-264

I-265

I-266

I-267

I-268

I-269

I-270

I-271

I-272

I-273

I-274

I-275

I-276

I-277

I-278

I-279

I-280

I-281

I-282

I-283

I-284

I-285

I-286

I-287

I-288

I-289

I-290

I-291

I-292

I-293

I-294

I-295

[0119] The compounds of this invention may be prepared in general bymethods known to those skilled in the art for analogous compounds, asillustrated by the general Schemes I, II, III, and IV shown below andthe Examples set forth infra.

[0120] Scheme I above shows a general method for preparingN′-alkyl-N-cyanoureas (3) useful in the preparation of the compounds ofthe present invention wherein Z is NH. At step (a), cyanamide (2) istreated with an alkyl isocyanate in aqueous sodium hydroxide to afford,after acidification, compound 3. One of skill in the art would recognizethat a variety of alkyl isocyanates would be amenable to the reactionconditions of Scheme I to form a variety of N′-alkyl-N-cyanoureas.

[0121] Reagents and conditions: (a) sodium perborate, HOAc, 55° C. (b)Ring A, NaH, THF; (c)NH₃, MeOH, EtOH, 80° C.; (d) R¹—B(OH)₂, Pd(PPh₃)₄,NaHCO₃, H₂O, THF, 70° C.; (e) H₂, Pd/C, EtOAc; (f) 3, H₂SO₄, 95° C.; (g)2-methyl-2-thiopseudourea, R²-chloroformate.

[0122] Scheme II above shows a general method for preparing thebenzimidazole compounds of the present invention wherein Z is NH or O.The bromo-aniline (4) is treated with sodium perborate and acetic acidto form the difluoro-nitro compound (5). Compound 5 is treated with RingA in the presence of sodium hydride to afford the bi-aryl compound 6.The remaining fluoro group of compound 6 is displaced with ammonia toform the amino compound (7). The 2-nitro-5-bromoaniline (7) is thencoupled to an aryl boronic acid, at step (d), in the presence ofpalladium to form the tri-aryl compound (8). The nitro group of compound8 is reduced to form a diamino compound which is treated with anN′-alkyl-N-cyanourea (3) to form benzimidazole compound of formula Iwherein Z is NH (9).

[0123] Alternatively, intermediate 8 may be used to form compounds offormula I wherein Z is O. Compound 10 is formed by treating 8, afterreduction to the diamino compound, with 2-methyl-2-thiopseudourea andR²-chloroformate according to the method described by L. I. Kruse et al,J. Med. Chem. 1989, 32, 409-417. One of ordinary skill in the art wouldrecognize that the reactions depicted in Scheme II above are amenable toa variety of R¹ and Ring A groups of the present invention.

[0124] In an alternative method, intermediate 8 is treated with eitherN,N-diethlycarboxy-2-methyl-2-thiopseudourea orN,N-diethlyureamido-2-methyl-2-thiopseudourea to form compounds 10 and9, respectively. The synthesese of bothN,N-diethlycarboxy-2-methyl-2-thiopseudourea andN,N-diethlyureamido-2-methyl-2-thiopseudourea are described in theExamples set forth infra.

[0125] Reagents and conditions: (a) Pd(dppf)Cl₂/KOAc, DMSO, 80° C.; and(b) Cu(OAc)₂/pyridine, DMF.

[0126] Scheme III above shows a general method for preparing compoundsof formula II-a using methods substantially similar to those describedby Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L., Tetrahedron Letters,vol. 40, (1999) 2657-2660. Compound 7 is treated with diboranic ester inthe presence of Pd(dppf)/potassium acetate in DMSO at 80° C. to affordintermediate 11. Compound 11 is treated with 4-C(O)N(R′)₂-imidazole inthe presence of copper acetate to form the 4-C(O)N(R′)₂-imidazol-1-ylcompound 12. Compounds of formula II-a are prepared from compound 12 asdescribed in Scheme II, steps (e), (f), and (g).

[0127] Although 4-C(O)N(R′)₂-imidazole is used to exemplify, one ofordinary skill in the art would recognize that a variety of R¹ groupsare amenable to the displacement reaction at step (c) to form a varietyof compounds of the present invention. Generally, the boronateintermediate 11 may be treated with a variety of R¹-halides orR¹-triflates, using methods well known to one of ordinary skill in theart, to form intermediate compounds 12′ as shown below. Using themethods recited herein and those known to one of ordinary skill in theart, compounds 12′ are useful for preparing compounds 9 and 10 of thepresent invention as depicted above at Scheme II.

[0128] Reagents and conditions: (a); (b) NH₄OH/dioxane, reflux; (c)Pd(PPh₃)₄/THF, reflux; and (d) Na₂CO₃/DMF, heat.

[0129] Scheme IV above shows an alternate method for preparing compoundsof formula II-a. Compound 13 is nitrated to form 14. Compound 14 istreated with ammonium hydroxide to form the amino compound 15. The bromogroup of compound 15 is treated with the BrZn-Ring A reagent in thepresence of Pd(PPh₃)₄ in THF to form compound 16. Compound 16 is treatedwith the 4-C(O)N(R′)₂-imidazole in the presence of sodium carbonate toform the 4-C(O)N(R′)₂-imidazol-1-yl compound 18. Compounds of formulaII-a are then prepared from compound 18 as described in Scheme II, steps(e), (f), and (g).

[0130] One of skill in the art would recognize that a variety ofcompounds of the present invention may be prepared according to thegeneral method of Schemes I, II, III, and IV, methods known in the art,and the synthetic Examples set forth below.

[0131] The compounds of this invention are potent inhibitors of gyraseand Topo IV as determined by enzymatic assay. These compounds have alsobeen shown to have antimicrobial activity in an antimicrobialsusceptibility assay. The activity of a compound utilized in thisinvention as an inhibitor of gyrase or Topo IV may be assayed in vitro,in vivo or in a cell line according to methods known in the art. Thedetails of the conditions used for both the enzymatic and theantimicrobial susceptibility assays are set forth in the Examples below.

[0132] According to another embodiment, the invention provides acomposition comprising a compound of this invention or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle. The amount of compound in thecompositions of this invention is such that is effective to detectablyinhibit gyrase, Topo IV, or to measurably decrease bacterial quantity,in a biological sample or in a patient. Preferably the composition ofthis invention is formulated for administration to a patient in need ofsuch composition. Most preferably, the composition of this invention isformulated for oral administration to a patient.

[0133] The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

[0134] Inhibition of gyrase and/or Topo IV activity in a biologicalsample is useful for a variety of purposes that are known to one ofskill in the art. Examples of such purposes include, but are not limitedto, blood transfusion, organ-transplantation, biological specimenstorage, and biological assays.

[0135] The term “patient”, as used herein, means an animal, preferably amammal, and most preferably a human.

[0136] The term “pharmaceutically acceptable carrier, adjuvant, orvehicle” refers to a non-toxic carrier, adjuvant, or vehicle that doesnot destroy the pharmacological activity of the compound with which itis formulated. Pharmaceutically acceptable carriers, adjuvants orvehicles that may be used in the compositions of this invention include,but are not limited to, ion exchangers, alumina, aluminum stearate,lecithin, serum proteins, such as human serum albumin, buffer substancessuch as phosphates, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

[0137] The term “detectably inhibit”, as used herein means a measurablechange in gyrase, or Topo IV, activity between a sample comprising saidcomposition and gyrase, or Topo IV, and an equivalent sample comprisinggyrase, or Topo IV in the absence of said composition.

[0138] As used herein, the term “measurably decrease bacterialquantity”, as used herein means a measurable change in the number ofbacteria between a sample containing said composition and a samplecontaining only bacteria.

[0139] A “pharmaceutically acceptable salt” means any non-toxic salt ofa compound of this invention that, upon administration to a recipient,is capable of providing, either directly or indirectly, a compound ofthis invention or an inhibitorily active metabolite or residue thereof.As used herein, the term “inhibitorily active metabolite or residuethereof” means that a metabolite or residue thereof is also an inhibitorof gyrase and/or Topo IV.

[0140] Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from pharmaceutically acceptableinorganic and organic acids and bases. Examples of suitable acid saltsinclude acetate, adipate, alginate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate,glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate,picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate,thiocyanate, tosylate and undecanoate. Other acids, such as oxalic,while not in themselves pharmaceutically acceptable, may be employed inthe preparation of salts useful as intermediates in obtaining thecompounds of the invention and their pharmaceutically acceptable acidaddition salts.

[0141] Salts derived from appropriate bases include alkali metal (e.g.,sodium and potassium), alkaline earth metal (e.g., magnesium), ammoniumand N⁺(C₁₋₄ alkyl)₄ salts. This invention also envisions thequaternization of any basic nitrogen-containing groups of the compoundsdisclosed herein. Water or oil-soluble or dispersible products may beobtained by such quatemization.

[0142] The compositions of the present invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

[0143] For this purpose, any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

[0144] The pharmaceutically acceptable compositions of this inventionmay be orally administered in any orally acceptable dosage formincluding, but not limited to, capsules, tablets, aqueous suspensions orsolutions. In the case of tablets for oral use, carriers commonly usedinclude lactose and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. For oral administration in a capsuleform, useful diluents include lactose and dried cornstarch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

[0145] Alternatively, the pharmaceutically acceptable compositions ofthis invention may be administered in the form of suppositories forrectal administration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

[0146] The pharmaceutically acceptable compositions of this inventionmay also be administered topically, especially when the target oftreatment includes areas or organs readily accessible by topicalapplication, including diseases of the eye, the skin, or the lowerintestinal tract. Suitable topical formulations are readily prepared foreach of these areas or organs.

[0147] Topical application for the lower intestinal tract can beeffected in a rectal suppository formulation (see above) or in asuitable enema formulation. Topically-transdermal patches may also beused.

[0148] For topical applications, the pharmaceutically acceptablecompositions may be formulated in a suitable ointment containing theactive component suspended or dissolved in one or more carriers.Carriers for topical administration of the compounds of this inventioninclude, but are not limited to, mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene, polyoxypropylenecompound, emulsifying wax and water. Alternatively, the pharmaceuticallyacceptable compositions can be formulated in a suitable lotion or creamcontaining the active components suspended or dissolved in one or morepharmaceutically acceptable carriers. Suitable carriers include, but arenot limited to, mineral oil, sorbitan monostearate, polysorbate 60,cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol andwater.

[0149] For ophthalmic use, the pharmaceutically acceptable compositionsmay be formulated as micronized suspensions in isotonic, pH adjustedsterile saline, or, preferably, as solutions in isotonic, pH adjustedsterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, for ophthalmic uses, thepharmaceutically acceptable compositions may be formulated in anointment such as petrolatum.

[0150] The pharmaceutically acceptable compositions of this inventionmay also be administered by nasal aerosol or inhalation. Suchcompositions are prepared according to techniques well-known in the artof pharmaceutical formulation and may be prepared as solutions insaline, employing benzyl alcohol or other suitable preservatives,absorption promoters to enhance bioavailability, fluorocarbons, and/orother conventional solubilizing or dispersing agents.

[0151] Most preferably, the pharmaceutically acceptable compositions ofthis invention are formulated for oral administration.

[0152] Dosage levels of between about 0.01 and about 100 mg/kg bodyweight per day, preferably between 0.5 and about 75 mg/kg body weightper day and most preferably between about 1 and 50 mg/kg body weight perday of the active ingredient compound are useful in a monotherapy forthe prevention and treatment of bacterial infections caused by bacteriasuch as Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcusfaecalis, Enterococcus faecium, Klebsiella pneumoniae, Enterobacter sps.Proteus sps. Pseudomonas aeruginosa, E. coli, Serratia marcesens,Staphylococcus aureus, Coag. Neg. Staph, Haemophilus influenzae,Bacillus anthracis, Mycoplasma pneumoniae, Moraxella catarralis,Chlamydia pneumoniae, Legionella pneumophila, Mycobacteriumtuberculosis, Staphylococcus epidermidis, or Helicobacter pylori.

[0153] Typically, the pharmaceutical compositions of this invention willbe administered from about 1 to 5 times per day or alternatively, as acontinuous infusion. Or, alternatively, the compositions of the presentinvention may be administered in a pulsatile formulation. Suchadministration can be used as a chronic or acute therapy. The amount ofactive ingredient that may be combined with the carrier materials toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. A typical preparation willcontain from about 5% to about 95% active compound (w/w). Preferably,such preparations contain from about 20% to about 80% active compound.

[0154] When the compositions of this invention comprise a combination ofa compound of formula I and one or more additional therapeutic orprophylactic agents, both the compound and the additional agent shouldbe present at dosage levels of between about 10% to 80% of the dosagenormally administered in a monotherapy regime.

[0155] Upon improvement of a patient's condition, a maintenance dose ofa compound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level, treatment should cease.Patients may, however, require intermittent treatment on a long-termbasis upon any recurrence or disease symptoms.

[0156] As the skilled artisan will appreciate, lower or higher dosesthan those recited above may be required. Specific dosage and treatmentregimens for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health status, sex, diet, time ofadministration, rate of excretion, drug combination, the severity andcourse of the disease, and the patient's disposition to the disease andthe judgment of the treating physician.

[0157] Depending upon the particular condition, or disease, to betreated or prevented, additional therapeutic agents, which are normallyadministered to treat or prevent that condition, may also be present inthe compositions of this invention. As used herein, additionaltherapeutic agents that are normally administered to treat or prevent aparticular disease, or condition, are known as “appropriate for thedisease, or condition, being treated”. Such agents include, but are notlimited to, an antibiotic, an anti-inflammatory agent, a matrixmetalloprotease inhibitor, a lipoxygenase inhibitor, a cytokineantagonist, an immunosuppressant, an anti-cancer agent, an anti-viralagent, a cytokine, a growth factor, an immunomodulator, a prostaglandin, an anti-vascular hyperproliferation compound, or an agent whichincreases the susceptibility of bacterial organisms to antibiotics.

[0158] Agents which increase the susceptibility of bacterial organismsto antibiotics are known. For example, U.S. Pat. No. 5,523,288, U.S.Pat. No. 5,783,561 and U.S. Pat. No. 6,140,306 describe methods of usingbactericidal/permeability-increasing protein (BPI) for increasingantibiotic susceptibility of gram-positive and gram-negative bacteria.Agents that increase the permeability of the outer membrane of bacterialorganisms have been described by Vaara, M. in Microbiological Reviews(1992) pp. 395-411, and the sensitization of gram-negative bacteria hasbeen described by Tsubery, H., et al, in J. Med. Chem. (2000) pp.3085-3092.

[0159] According to another embodiment, the invention provides a methodfor treating or lessening the severity of a bacterial infection in apatient comprising the step of administering to said patient acomposition according to the present invention.

[0160] According to another embodiment, the invention provides a methodof inhibiting gyrase in a biological sample.

[0161] According to another embodiment, the invention provides a methodof inhibiting Topo IV in a biological sample.

[0162] According to another embodiment, the invention provides a methodof decreasing bacterial quantity in a biological sample.

[0163] According to another embodiment, the invention provides a methodof decreasing bacterial quantity in a biological sample, but furthercomprising the step of contacting said biological sample with an agentwhich increases the susceptibility of bacterial organisms toantibiotics.

[0164] The pharmaceutical compositions and methods of this inventionwill be useful generally for controlling bacterial infections in vivo.Examples of bacterial organisms that may be controlled by thecompositions and methods of this invention include, but are not limitedto, the following organisms: Streptococcus pneumoniae, Streptococcuspyogenes, Enterococcus faecalis, Enterococcus faecium, Kiebsiellapneumoniae, Enterobacter sps. Proteus sps. Pseudomonas aeruginosa, E.coli, Serratia marcesens, Staphylococcus aureus, Coag. Neg. Staph,Haemophilus infuenzae, Bacillus anthracis, Mycoplasma pneumoniae,Moraxella catarralis, H. influenzae, Chlamydia pneumoniae, Legionellapneumophila, Mycobacterium tuberculosis, Helicobacter pylori,Staphylococcus epidermidis. Chlamydia pneumoniae, Legionellapneumophila, Mycobacterium tuberculosis, or Helibacter pylori.

[0165] The compositions and methods will therefore be useful forcontrolling, treating or reducing the advancement, severity or effectsof nosocomial or non-nosocomial infections. Examples of nosocomial usesinclude, but are not limited to, urinary tract infections, respiratoryinfections such as pneumonia, surgical wound infections, and bloodstream infections (also known as bacteremia). Examples of non-nosocomialuses include but are not limited to urinary tract infections, pneumonia,prostatitis, skin and soft tissue infections, intra-abdominalinfections, and therapy for febrile neutropenic patients.

[0166] The term “pharmaceutically effective amount” refers to an amounteffective in treating or ameliorating a bacterial infection in apatient. The term “prophylactically effective amount” refers to anamount effective in preventing or substantially lessening a bacterialinfection in a patient.

[0167] The compounds of this invention may be employed in a conventionalmanner for controlling bacterial infections levels in vivo and fortreating diseases or reducing the advancement or severity of effectswhich are mediated by bacteria. Such methods of treatment, their dosagelevels and requirements may be selected by those of ordinary skill inthe art from available methods and techniques.

[0168] For example, a compound of this invention may be combined with apharmaceutically acceptable adjuvant for administration to a patientsuffering from a bacterial infection or disease in a pharmaceuticallyacceptable manner and in an amount effective to lessen the severity ofthat infection or disease.

[0169] Alternatively, the compounds of this invention may be used incompositions and methods for treating or protecting individuals againstbacterial infections or diseases over extended periods of time. Thecompounds may be employed in such compositions either alone or togetherwith other compounds of this invention in a manner consistent with theconventional utilization of enzyme inhibitors in pharmaceuticalcompositions. For example, a compound of this invention may be combinedwith pharmaceutically acceptable adjuvants conventionally employed invaccines and administered in prophylactically effective amounts toprotect individuals over an extended period of time against bacterialinfections or diseases.

[0170] The compounds of formula I may also be co-administered with otherantibiotics to increase the effect of therapy or prophylaxis againstvarious bacterial infections. When the compounds of this invention areadministered in combination therapies with other agents, they may beadministered sequentially or concurrently to the patient. Alternatively,pharmaceutical or prophylactic compositions according to this inventioncomprise a combination of a compound of formula I and anothertherapeutic or prophylactic agent.

[0171] The additional therapeutic agents described above may beadministered separately, as part of a multiple dosage regimen, from theinhibitor-containing composition. Alternatively, these agents may bepart of a single dosage form, mixed together with the inhibitor in asingle composition.

[0172] In order that this invention be more fully understood, thefollowing examples are set forth. These examples are for the purpose ofillustration only and are not to be construed as limiting the scope ofthe invention in any way.

EXAMPLES Example 1

[0173] 5-Bromo-1,3-difluoro-2-nitro-benzene: To a suspension of sodiumperborate tetrahydrate (1.04 g, 5 mmol) in acetic acid (20 mL), stirredat 55° C., was added a solution of 4-bromo-2,6-difluoroaniline in aceticacid (10 mL) over 1 hour in a dropwise fashion. After stirring at 55° C.for an additional 3 hours, the solution was allowed to cool to roomtemperature and filtered. The filtrate was poured into ice, andextracted twice with ethyl acetate. The combined organic extracts werewashed successively with 5×100-mL portions of water, brine, dried(MgSO₄), and concentrated in vacuo. The resulting residue was purifiedby column chromatography over silica gel eluted with ethylacetate:hexanes (1:20) to afford 780 mg of the titel compound as a tansolid. ¹H NMR (CDCl₃) δ 7.32 (dt, 2H).

Example 2

[0174] 1-(5-Bromo-3-fluoro-2-nitro-phenyl)-1H-pyrazole: To a suspensionof sodium hydride (44 mg, 1.1 mmol, 60% oil dispersion) in THF (4 mL),stirred at 0° C., was added a solution of pyrazole (72 mg, 1.05 mmol) inTHF (1 mL). The resulting mixture was stirred at 0° C. for 5 minutes anda solution of 5-bromo-1,3-difluoro-2-nitro-benzene (238 mg, 1 mmol) inTHF (1 mL) was added. The mixture was stirred at room temperature for 1hour, quenched by addition of water (1 mL), then partitioned betweenwater (20 mL) and ethyl acetate (50 mL). The organic layer was washedwith brine, dried (MgSO₄), and concentrated in vacuo. The residue waspurified by column chromatography over silica gel eluted with ethylacetate:hexanes (1:6), to afford 240 mg (86%) of the title compound.

[0175]¹H NMR (CDCl₃) δ 6.55 (t, 1H), 7.45 (d, 1H), 7.60 (s, 1H), 7.80(m, 2H). MS M+1 287, M+1+2 289.

Example 3

[0176] 5-Bromo-2-nitro-3-pyrazol-1-yl-phenylamine: To a solution of1-(5-bromo-3-fluoro-2-nitro-phenyl)-1H-pyrazole (240 mg, 0.84 mmol) inethanol (3 mL) was added ammonia (3 mL, 2N in methanol. The resultingmixture was heated in a sealed tube at 80° C. for 16 hours thenconcentrated in vacuo. The residue was purified by column chromatographyover silica gel eluted with ethyl acetate:hexanes (1:3) to afford 205 mg(86%) of the title compound as a yellow solid. ¹H NMR (CDCl₃) δ 5.20 (brs, 2H), 6.50 (t, 1H), 6.9 (d, 1H), 7.1 (d, 1H), 7.7 (d, 1H), 7.8 (d,1H). MS M+1 283, M+1+2 285.

Example 4

[0177] 2-Nitro-3-pyrazol-1-yl-5-pyridin-3-yl-phenylamine: To a solutionof 5-bromo-2-nitro-3-pyrazol-1-yl-phenylamine (200 mg, 0.71 mmol) in THF(8 mL) was added, successively, 3-pyridyl-diethyl borane (157 mg),(tetrakistriphenylphosphine) palladium(0) (84 mg), and sodium carbonate(1.1 mL, 2.2 mmom of 2M aqueous). The resulting mixture was stirred at70° C. overnight then cooled to room temperature. The reaction mixturewas diluted with ethyl acetate (100 mL) and washed with water (50 mL),brine (50 mL), dried (MgSO₄) then concentrated in vacuo. The resultingresidue was purified by column chromatography over silica gel elutedwith a gradient of ethyl acetate:hexanes (1:3, 1:2, 1:0, 2:1, 4:1, 8:1),to afford 120 mg (60%) of the title compound as a yellow solid. ¹H NMR(DMSO-d₆) δ 6.45 (br,s 2H), 6.55 (t, 1H), 7.1 (s, 1H), 7.25 (s, 1H),7.55 (m, 1H), 7.7 (s, 1H), 8.1 (dt, 1H), 8.3 (d, 1H), 8.7 (d, 1H), 8.9(s, 1H).

Example 5

[0178]1-Ethyl-3-(7-pyrazol-1-yl-5-pyridin-3-yl-1H-benzoimidazol-2-yl)-urea(I-2): A suspension of 2-nitro-3-pyrazol-1-yl-5-pyridin-3-yl-phenylamine(120 mg, 0.40 mmol) and 10% palladium on carbon (12 mg) in ethyl acetate(10 mL) was placed in a Parr hydrogenator under a hydrogen pressure of45 psi. The mixture was shaken for 16 hours, filtered and the filtrateconcentrated in vacuo. The resulting residue was diluted with H₂SO₄ (1.6mL or 1N), and N′-ethyl-N-cyanourea (0.8 mL, 1M) was added. The mixturewas heated at 95° C. for 4 hours then concentrated in vacuo. The residuewas purified by preparative HPLC to afford 75 mg of the title compoundas the bis-TFA salt which was converted to the free base to afford thetitle compound. ¹H NMR (DMSO-d₆) δ 1.1 (t, 3H), 3.2 (m, 2H), 7.0 (m,1H), 7.3 (d, 1H), 7.5 (m, 1H), 7.55 (s, 1H), 8.0 (d, 1H), 8.55 (dd, 1H),8.85 (s, 1H), 10.1 (s, 1H), 12.0 (s, 1H). LC/MS one peak, M+1 348.23,M−1 346.18.

Example 6

[0179] N′-Ethyl-N-cyanourea: To a 20° C. solution of sodium hydroxide(1.5 M aqueous, 50 mL, 75.02 mmol) was added cyanamide (8.5 g, 202.25mmol) then ethyl isocyanate (4 mL, 50.56 mmol) was added in a dropwisefashion over 10 minutes. After stirring for 30 minutes, additionalsodium hydroxide (3M, 25 mL. 75.02 mmol) and ethyl isocyanate (4 mL,50.56 mmol) were added. The resulting solution was then aged for aminimum of 30 minutes before using directly without isolation.

Example 7

[0180] 4-(Pyridin-3-yl)-2-nitroaniline: To a solution of4-bromo-2-nitroaniline (4.8 g, 22 mmol) in DME (100 mL) was addedpyridine-3-boronic acid 1,3-propanediol cyclic ester (4 g, 24 mmol),sodium bicarbonate (45 mL, 1M), andtetrakis(triphenylphosphine)palladium (0.05 eq). The resulting mixturewas heated at 90° C. for 8 hours then cooled to room temperature. Thesolids were collected, washed with water, 5% EtOAc in Hexane and driedto afford the title compound (5 g). ¹H NMR (CDCl₃) δ 8.8 (d, 1H), 8.55(m, 1H), 8.35 (d, 1H), 7.85 (dd, 1H), 7.65 (dd, 1H), 7.35 (m, 1H), 6.95(d, 1H), 6.25 (br s, 2H).

Example 8

[0181] 2-Bromo-6-nitro-4-pyridin-3-yl-phenylamine: To a solution of4-(pyridin-3-yl)-2-nitroaniline (1.3 g, 9 mmol) in HOAc (25 mL) wasadded bromine (1.58 g, 9.9 mmol) in HOAc (5 mL). The resulting mixturewas stirred at room temperature for one hour and then quenched withice-water. The solids were collected, washed with water and dried. Thesolids in EtOAc was then washed with NaOH (2N; 20 mL), water, brine andconcentrated in vacuo. The concentrate was purified by chromatography[Silica Gel, ethyl acetate:hexanes (1:1)] to afford the title compound(0.8 g). ¹H NMR (CDCl₃) δ 8.83 (d, 1H), 8.55 (m, 1H), 8.41 (d, 1H), 8.15(d, 1H), 7.96 (m, 1H), 7.41 (m, 1H), 6.80 (br s, 2H). (M+1) 294.

Example 9

[0182] 2-Nitro-6-pyridin-2-yl-4-pyridin-3-yl-phenylamine: A mixture of2-bromo-6-nitro-4-pyridin-3-yl-phenylamine (100 mg, 1 eq), 2-pyridylznicbromide (6 eq) and tetrakis(triphenylphosphine)palladium (0.1 eq) in THF(10 mL) was heated at 100° C. for 18 hours. The reaction was quenchedwith water (2 mL). The product was extracted with EtOAc (20×3). Thecombined organic layer was then concentrated in vacuo and the residuewas purified by chromatography (Silica Gel, EtOAC) to afford the titlecompound (75 mg) as a yellow solid. (M+1) 293.

Example 10

[0183] 3-Pyridin-2-yl-5-pyridin-3-yl-benzene-1,2-diamine: To a solutionof 2-nitro-6-pyridin-2-yl-4-pyridin-3-yl-phenylamine (75 mg, 0.26 mmol)in ethyl acetate (20 mL) was added 10% palladium on carbon (50 mg). Theresulting suspension was placed in a Parr hydrogenation apparatus under40 psi hydrogen gas while shaking at ambient temperature for one hour.The catalyst was removed by filtration and the filtrate concentrated invacuo to afford compound the title compound (50 mg, 0.19 mmol).

Example 11

[0184]1-Ethyl-3-(7-pyridin-2-yl-5-pyridin-3-yl-1H-benzoin-dazol-2-yl)-urea(I-31): To a solution 3-pyridin-2-yl-5-pyridin-3-yl-benzene-1,2-diamine(50 mg, 0.19 mmol) and sulfuric acid (0.76 mL, 1 N) in water (1 mL) wasadded N′-ethyl-N-cyanourea (0.76 mL, 1 M). Enough sulfuric acid wasadded dropwise to achieve pH 3. The resulting mixture was heated at 100°C. for 8 hours. The reaction mixture was then cooled to ambienttemperature. The solids were collected, washed with water and dried. Thesolids were purified by chromatography (Silica Gel, EtOAc, then 10% MeOHin EtOAc) to afford compound 5 (27 mg). ¹H NMR (CDCl₃) δ 8.92 (d, 1H),8.80 (m, 1H), 8.52 (m, 1H), 8.30 (m, 1H), 8.21 (d, 1H), 8.04 (s, 1 H),7.94 (m, 1H), 7.75 (s, 1H), 7.56 (d, 1H), 7.37 (m, 2H), 3.36 (q, 2H),1.24 (t, 3H). (M+1) 359.

Example 12

[0185]

[0186] 2,2-Dimethyl-N-(2-pyrimidin-2-yl-phenyl)-propionamide: A 5 Lflask was charged with the above depicted boronic acid as a tetrahydrate(281.4 grams, 960 mmoles), 2-chloropyrimidine (100 g, 874 mmoles),NaHCO₃ (146.8 grams, 1.746 moles), and Pd(PPh₃)₄ (10.0 grams, 8.72mmoles). Water (1 L) and dimethoxyethane (1 L) were added, and themixture was heated slowly to 83° C. (internal temperature) over a 1 hourperiod with overhead stirring. After ˜2 hours all solids had dissolved.The reaction was allowed to stir for 8 hours. The mixture was cooled toroom temperature and stirred overnight after which time a thickprecipitate had formed. The crude mixture was diluted with water (2 L)and stirred for an additional 2 hours after which time the mixture wasfiltered and the solids were washed sequentially with water, 0.1 N NaOH,and water again. The solids were then dried under high vacuum at 50° C.to afford the title compound (˜233 grams) as a tan powder.

Example 13

[0187]

[0188] N-(4-Bromo-2-pyrimidin-2-yl-phenyl)-2,2-dimethyl-propionamide: Toa room temperature suspension of2,2-dimethyl-N-(2-pyrimidin-2-yl-phenyl)-propionamide (˜117 grams, 437mmoles) in acetic acid (1 L) was added bromine (67 mL, 1.31 moles) as asolution in 100 mL of acetic acid over a 1 hour period. The heterogenousmixture was stirred at room temperature for 5 hours over which time athick precipitate formed. The mixture was then poured over ice, dilutedwith 1N Na₂S₂O₃ (2 L), and stirred for 1 hour. The solids were filtered,resuspended in water (2 L), stirred for 1 hour, then filtered and washedwith water again. The resulting solids were pumped to dryness at 50° C.,resuspended in HOAc (1 L), and treated with bromine (22 mL, 430 mmoles)in acetic acid solution (20 mL) over a 20 minute period. The resultingheterogenous mixture was stirred for 5 hours, then quenched and treatedas described above. The resulting solids were vacuum dried at 50° C. toafford the title compound (165 grams) as a tan powder.

Example 14

[0189]

[0190]N-(4-Bromo-2-nitro-6-pyriidin-2-yl-phenyl)-2,2-dimethyl-propionamide: Toa 5° C. suspension ofN-(4-bromo-2-pyrimidin-2-yl-phenyl)-2,2-dimethyl-propionamide (32.6grams, 97.5 mmoles) in TFA (400 mL) was added 90% nitric acid (70 mL,1.46 mmoles) over a 30 minute period. The mixture was then allowed towarm to room temperature and stir for a total of 2 hours. The crudereaction (now homogenous) was poured into ice producing a pasty mass.The mixture was diluted to 2 L total volume with water, treated with 500mL of methanol, and vigorously stirred for 12 hours. The resultingsolids were filtered, washed with copious amounts of water, then vacuumdried at 50° C. to afford the title compound (29.9 grams, 81% yield) asa tan powder.

Example 15

[0191]

[0192] 4-Bromo-2-nitro-6-pyrimidin-2-yl-phenylaniine: A suspension ofN-(4-bromo-2-nitro-6-pyrimidin-2-yl-phenyl)-2,2-dimethyl-propionamide(29.9 grams, 78.8 mmoles) in conc. HCl (200 mL) was refluxed for 8hours. The partially homogeneous crude reaction was then cooled to roomtemperature, diluted with water (500 mL), and the resulting precipitatewas stirred for 1 hour. The solids were then filtered, washed withwater, and vacuum dried at 50° C. to afford the title compound (21.1grams, 91% yield) as an orange powder.

Example 16

[0193]

[0194]2-Nitro-6-pyrimidin-2-yl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine:A mixture of 4-bromo-2-nitro-6-pyrimidin-2-yl-phenylamine (1.82 g, 6.2mmol), bis(pinacolato)diboron (3.144 g, 12.4 mmol), PdCl₂dppf₂ (453 mg,0.6 mmol) and KOAc (3.03 g, 31 mmol) in dioxane (60 ml) was heated at105° C. for 2.5 hours. The reaction was filtered and washed withdichloromethane. The combined filtrates were concentrated under vacuumand water (100 ml) was added to the residue. Extraction withdichloromethane (3×50 ml), drying and concentration gave a residue,which was washed with ether-hexane to afford the title compound (2.07 g,98%).

Example 17

[0195]

[0196] N-[2-(3-Fluoro-pyridin-2-yl)-phenyl]-2,2-dimethyl-propionamide: A3 L flask was charged with the above depicted boronic acid as atetrahydrate (92.1 grams, 314 mmoles), chlorofluoropyridine (37.6 g, 286mmoles), NaHCO₃ (48.0 grams, 572 mmoles), and Pd(PPh₃)₄ (3.3 grams, 2.86mmoles). Water (300 mL) and dimethoxyethane (300 mL) were added, and themixture was heated slowly to 83° C. (internal temperature) over a 1 hourperiod with overhead stirring. After ˜2 hours all solids had dissolved.The reaction was allowed to stir for 10 hours. The mixture was cooled toroom temperature and stirred overnight after which time a thick gum hadformed. The crude mixture was diluted with water (2 L) and stirred foran additional 2 hours. The mixture was then allowed to rest withoutstirring until the gum had settled to the bottom of the flask. Theliquid phase was removed via vacuum, then replaced with 0.1 N NaOH andstirred for 15 minutes. The gum was allowed to settle and the liquidremoved via vacuum. The gum was then similarly washed three times withwater, then transferred to a 1 neck flask as an acetone solution. Themixture was concentrated in vacuo and azeotroped five times with ethylacetate.

Example 18

[0197]

[0198]N-[4-Bromo-2-(3-fluoro-pyridin-2-yl)-phenyl]-2,2-dimethyl-propionamide:To a room temperature suspension ofN-[2-(3-fluoro-pyridin-2-yl)-phenyl]-2,2-dimethyl-propionamide (˜77mmoles) in acetic acid (300 mL) was added bromine (12 mL, 228 mmoles) asa solution in 50 mL of acetic acid over a 1 hour period. Theheterogenous mixture was stirred at room temperature for 5 hours overwhich time a thick precipitate formed. The mixture was then poured overice, diluted with 1N Na₂S₂O₃ (500 mL), and stirred for 1 hour. Thesolids were filtered, re-suspended in water (2 L), stirred for 1 hour,then filtered and washed with water again. The resulting solids werepumped to dryness at 50° C., re-suspended in HOAc (400 mL), and treatedwith bromine (4 mL, 76 mmoles) in acetic acid solution (20 mL) over a 20minute period. The resulting heterogenous mixture was stirred for 5hours, then quenched and treated as described above. The resultingsolids were vacuum dried at 50° C. to afford the title compound (19.1grams, 72%) as a tan powder.

Example 19

[0199]

[0200]N-[4-Bromo-2-(3-fluoro-pyridin-2-yl)-6-nitro-phenyl]-2,2-dimethyl-propionamide:To a suspension ofN-[4-bromo-2-(3-fluoro-pyridin-2-yl)-phenyl]-2,2-dimethyl-propionamide(6.45 grams, 18.4 mmoles) in TFA (100 mL) and TFAA (25.5 mL, 183.6mmole), at 0° C., was added a TFA solution (30 mL) of 90% fuming nitricacid (2.46 mL, 55.1 mmoles) over a 45 minute period. The mixture wasthen stirred at 0° C. for a total of 4 hours. The crude reaction (nowhomogenous) was poured into ice producing a pasty mass. The mixture wasdiluted to 500 mL total volume with water, treated with 50 mL ofmethanol, and vigorously stirred for 12 hours. The resulting solids werefiltered, washed with copious amounts of water, then dried in vacuo at50° C. to afford the title compound (6.1 grams, 82% yield) as a tanpowder.

Example 20

[0201]

[0202] 2-(3,5-Difluoro-phenyl)-pyrimidine: A solution of thedifluoroboronic acid (5.4 g, 34.1 mmoles) and 2-chloropyrimidine (3.0 g,26.2 mmoles) in ethanol (50 mL) was treated with Na₂CO₃ (3.6 g, 34.1mmoles) and Pd(PPh₃)₄ (1.5 g, 1.31 mmoles) then heated at reflux for 3days. The resulting mixture was then diluted with EtOAc, Silica geladded, and the resulting slurry stirred for 3 hours at room temperature.The crude mixture was then filtered through a silica gel pad with EtOAc,concentrated in vacuo, and flash chromatographed (silica gel,19/1-14/1-9/1-7/1 hexanes/EtOAc gradient) to afford the title compound(1.38 g, 27%) as a white solid. ¹H NMR (dmso-d₆, 500 MHz): 8.95 (d, 2H);7.98 (m, 2H); 7.57 (dd, 1H); 7.48 (m, 1H).

Example 21

[0203]

[0204] 2-(3,5-Difluoro-2-nitro-phenyl)-pyrimidine: To a room temperaturesolution of 2-(3,5-difluoro-phenyl)-pyrimidine (1.2 g, 6.24 mmole) inH₂SO₄ (3 mL) was added 90% HNO₃ (0.375 mL, 9.37 mmoles) over 10 secondsvia syringe. The resulting mixture was stirred at room temperature for 1hour then poured into ice. The resulting heterogeneous mixture was thendiluted with water, warmed to room temperature, and filtered. The solidswere washed with water and dried in vacuo to afford the title compound(1.53 g, 100%) as a tan solid. ¹H NMR (dmso-d₆, 500 MHz): 8.92 (d, 2H);8.67 (m, 1H); 7.94(m, 1H); 7.65 (dd, 1H).

Example 22

[0205]

[0206] 5-Fluoro-2-nitro-3-pyrimidin-2-yl-phenylamine: To a solution of2-(3,5-difluoro-2-nitro-phenyl)-pyrimidine (1.5 g, 6.32 mmoles) indioxane (10 mL) was added tBuNH₂ (6.6 mL, 63.24 mmoles) at roomtemperature. The mixture was heated to 100° C. in a sealed tube for 10hours. The mixture was then cooled to room temperature, poured intowater, and the solids stirred for 1 hour. The mixture was filtered,solids washed with water until filtrate was clear. The crude product wasthen diluted in MeOH, 6N HCl added, and the resulting mixture heated atreflux for 3 hours. The reaction was cooled to room temperature andpoured into ice. The resulting heterogeneous mixture was warmed to roomtemperature, filtered, solids washed with water until filtrate ranclear, and dried in vacuo to afford the title compound (1.33 g, 90%) asan orange powder. ¹H NMR (dmso-d₆, 500 MHz): 8.87 (d, 2H); 7.52 (dd,1H); 7.08 (dd, 1H); 6.86 (dd, 1H); 6.60 (s, 2H).

Example 23

[0207]

[0208]1-(3-Amino-4-nitro-5-pyrimidin-2-yl-phenyl)-1-imidazole-4-carboxylicacid cyclopropylamide: To a mixture of5-fluoro-2-nitro-3-pyrimidin-2-yl-phenylamine (650 mg, 2.77 mmole) inDMF (5 mL) was added 17 (545 mg, 3.6 mmoles) and Na₂CO₃ (381 mg, 3.60mmoles) at room temperature. The resulting mixture was heated to 125° C.for 6 hours, then cooled to room temperature. The resulting mixture wasdiluted with water and the yellow precipitate was stirred for 1 hour.The crude reaction was filtered and the solids washed with water untilthe filtrate ran clear. The washed solids were then dried in vacuo toafford the title compound (960 mg, 95%) as a yellow powder. ¹H NMR(dmso-d₆, 500 MHz): 8.91 (d, 1H); 8.42 (s, 1H); 8.29 (s, 1H); 8.08 (d,1H); 7.52 (dd, 1H); 7.36 (d, 1H); 7.29 (d, 1H); 6.59 (s, 2H); 2.89 (m,1H); 0.072 (m, 2H); 0.64 (m, 2H).

Example 24

[0209]

[0210] N,N-Diethlycarboxy-2-methyl-2-thiopseudourea: To a mixture of2-methyl-2-thiopseudourea sulfate (22.8 g, 81.9 mmol) in methylenechloride (200 mL)was added triethylamine (34.5 mL, 245.7 mmol) and ethylchloroformate (20.65 g, 245 mmol). After stirring over night the mixturewas washed with water, brine then dried over sodium sulfate, filteredand concentrated in vacuo to a pungent oil which was flashchromatagraphed (10% ethyl acetate/hexanes) to provide the titlecompound (16.68 g, 86.9% Y) as a colorless oil which solidified onstanding. ¹H NMR (500 Mhz, CDCl₃) ∂1.3(q,6H), 2.41(s,3H), 4.22(m,4H).

Example 25

[0211]

[0212] N,N-Diethlyureamido-2-methyl-2-thiopseudourea: To a mixture of2-methyl-2-thiopseudourea sulfate (2.0 g, 7.18 mmol) in water (3 mL) wasadded ethyl isocyanate (1.137 mL, 14.37 mmol) followed by dropwise 6NNaOH to a stable pH 8. After 1 hour at pH8 the biphasic solution wasdiluted with aqueous saturated sodium bicarbonate and extracted intoethyl acetate (3×100 mL). The combined organic layers were washed withbrine and dried over sodium sulfate, filtered then concentrated in vacuoto afford the title compound as a pungent oil (1.54 g, 92.7%). TLC (50%Ethyl acetate/methylene chloride) and ¹H NMR suggests that the materialis a mixture of mono and diacyl pseudourea. ¹H NMR (500 Mhz, CDCl₃)∂1.18(m2,6H), 2.31 and 2.41 (2s,3H), 3.28(m,4H).

Example 26

[0213]

[0214][5-(4-Cyclopropylcarbamoyl-imidazol-1-yl)-7-pyrimidin-2-yl-1H-benzoimidazol-2-yl]-carbamicacid ethyl ester: To a solution of1-(3-amino-4-nitro-5-pyrimidin-2-yl-phenyl)-1H-imidazole-4-carboxylicacid cyclopropylamide (65 mg, 0.178 mmoles) in MeOH (10 mL) was addedRa—Ni (2 drops of water slurry, catalytic) and the resulting suspensionwas placed under 45 psi of H₂ (Parr shaker) for 2 hours. The resultingmixture was then filtered, concentrated, diluted with 3 mL of pH=3.5buffer (made from 1M H₂SO₄ with enough NaOAc to raise pH to 3.5), andtreated with N,N-diethlycarboxy-2-methyl-2-thiopseudourea (0.267 mL of a1M solution of N,N-diethlycarboxy-2-methyl-2-thiopseudourea in dioxane)at room temperature. The resulting mixture was refluxed for 5 hoursresulting in a heterogeneous suspension. The reaction was cooled to roomtemperature, diluted with water and enough NH₄OH to raise the pH to˜6.0. The solids were then filtered and washed sequentially with water,2/1 water/ethanol, EtOAc, and then hexanes. The resulting solids weresuspended in MeOH, 2 equivalents of methanesulfonic acid was added, andconcentrated in vacuo to afford the title compound (75, 70%) as anoff-white solid. ¹H NMR (dmso-d₆, 500 MHz): 9.28 (s, 1H); 9.08 (d, 1H);8.8-7.4 (v. broad s, 4H); 8.67 (s, 1H); 8.53 (s, 1H); 8.46 (d, 1H); 8.05(d, 1H); 7.59 (dd, 1H); 4.33 (q, 2H); 2.88 (m, 1H); 2.35 (s, 6H); 1.34(t, 3H); 0.76 (m, 2H); 0.61 (m, 2H).

Example 27

[0215] We have prepared other compounds of formula I by methodssubstantially similar to those described in Schemes I through IV,Examples 1 through 26, and by methods known in the art. Thecharacterization data for these compounds is summarized in Table 3 belowand includes LC/MS (observed) and ¹H NMR data.

[0216]¹H NMR data is summarized in Table 3 below wherein ¹H NMR data wasobtained at 500 MHz in deuterated DMSO, unless otherwise indicated, andwas found to be consistent with structure. Compound numbers correspondto the compound numbers listed in Table 2. TABLE 3 Characterization Datafor Selected Compounds of Formula I Compound M − 1 M + 1 No. I- (obs)(obs) ¹H NMR 16 347.2 349.2 1.1(t, 3H) 3.2(q, 2H) 6.8(t, 1H) 7.5 (m,1H), 7.7(s, 1H) 7.9(s, 1H) 8.1(d, 1H) 8.3(s, 1H) 8.6(d, 1H) 8.9(s, 1H)9.6(s, 1H) 10.3(s, 1H) 20 360.3 362.3 (CD₃OD): 8.89(dd, 1H); 8.51(dd,1H); 8.42-8.29(br. s, 1H), 8.18(ddd, 1H); 7.94-7.77(br. s, 1H); 7.63(br.s); 7.58 (br. s, 1H); 7.53(dd, 1H); 3.32(q, 2H); 2.21(s, 3H); 1.23(t,3H) 24 391.3 393.3 1.13(t, 3H), 1.3(t, 3H) 3.24(q, 2H), 3.37(q, 2H),7.82(s, 1H), 7.82(s1H), 7.96(t, 1H) 8.19(s, 1H), 8.56(s, 1H), 8.62(d,1H), 8.82(d, 1H), 9.15(s, 1H), 11.02(s, 1H) 42 390.3 392.2 1.13(t, 3H)2.45(s, 3H) 3.23(q, 2H) 3.46(s, 3H) 6.58(m, 4H), 7.78(m, 3H) 9.11(s, 1H)10.51(s, 1H) 12.18(s, 1H) 43 — — 1.15(t, 3H), 3.25(m, 2H), 3.35(s, 3H),4.6(s, 2H), 7.4(br s, 1H), 7.55(s, 1H), 7.8(m, 1H), 8.0(d, 1H), 8.05(d,1H), 8.6(m, 1H), 8.7(m, 1H), 9.2(s, 1H), 10.4(br s, 1H) 49 — — 1.3(t,3H), 4.3(q, 2H), 6.65(t, 1H), 7.75 (d, 1H), 7.85(dd, 1H), 7.9(s, 1H),8.05 (d, 1H), 8.5(d, 1H), 8.75(dd, 1H), 9.1 (s, 1H), 11.7(br s, 1H), 50377.2 379.1 1.23(t, 3H), 2.89(s, 3H), 3.36(q, 2H), 7.93(d, 1H), 8.16(d,1H), 8.26(d, 1H), 8.33(d, 1H), 8.86(d, 1H), 8.97(d, 1H), 9.30(d, 1H) 51— — 1.1(t, 3H), 1.25(t, 3H), 3.25(q, 2H), 3.37(s, 3H), 4.05(q, 2H),6.6(m, 4H), 7.65(s, 1H), 7.9(m, 2H) 9.1(br s, 1H), 10.2(br s, 1H),11.8(br s, 1H) 54 — — 0.5(m, 2H), 0.8(m, 2H), 2.7(m, 1H), 6.4(br s, 1H),6.7(m, 1H), 7.75(s, 1H), 7.8(m, 1H), 7.85(s, 1H), 8.05(m, 1H), 8.5(brs,1H), 8.7(m, 1H), 9.05(s, 1H), 9.15(s, 1H), 10.2(br s, 1H) 55 — — 1.15(t,3H), 3.25(m, 2H), 7.25(m, 1H), 7.5(br s, 1H), 7.7(m, 1H), 7.85(s, 1H),8.3(s, 1H), 8.4(m, 1H), 8.7(m, 2H), 8.85(s, 1H), 9.1(s, 1H), 9.15(dd,1H), 10.5(br s, 1H), 57 377.1 379.2 9.08(d, 1H); 8.48(br. s, 1h); 8.13,(d, 1H); 7.95(d, 1H); 7.88(s, 1H); 7.25(d, 1H); 6.75(d, 1H); 6.64(s,1H);, 6.62(dd, 1H); 6.4-5.7(br. s, 2H); 5.69(q, 2H); 3.48(s, 3H);1.48(t, 3H) 61 — — 1.13(t, 3H) 2.38(s, 3H) 3.24(q, 2H) 5.36(s, 2H)6.71(m, 2H), 6.83(s, 1H) 7.18(d, 2H) 7.28(t, 1H) 7.38(m, 2H) 7.76(s, 1H)7.92(s, 2H), 8.30(s, 1H) 9.08(s, 1H) 11.50(s, 1H) 62 404.3 406.3 12.15,11.81(s, 1H), 10.34, 9.99(s, 1H), 9.13, 8.99(s, 1H), 7.99-7.81(m, 3H),7.68(s, 1H), 7.30-6.59(m, 4H), 5.09(m, 1H), 3.23(t, 2H), 1.339(d, 6H),1.13(t, 3H) 63 — — 1.15(t, 3H) 2.44(s, 3H) 3.25(q, 2H) 5.44(s, 2H)6.70(m, 3H), 7.40(d, 1H) 7.49(t, 1H) 7.75(s, 1H) 7.85(m, 1H) 7.97(s, 2H)8.12(s, 1H), 8.60(d, 1H) 9.09(s, 1H) 11.21(s, 1H) 64 — — 1.2(t, 3H),2.2(m, 2H), 3.3(m, 2H), 3.65(m, 2H), 4.1(t, 2H), 7.75(s, 1H), 7.84(s,1H), 7.87(s, 1H), 7.8(m, 1H), 8.5(m, 1H), 8.65(m, 1H), 9.0(s, 1H) 65423.1 425.1 (MeOH-d₄ & CDCl₃): 8.30-7.85(m, 4H), 6.78(s, 1H), 6.58(s,1H), 3.60(s, 3H), 3.37(q, 2H), 2.80(s, 3H), 1.25(t, 3H) 67 — — 1.15(t,6H), 3.45(q, 4H), 6.7(s, 1H), 7.7(m, 2H), 7.9(s, 1H), 8.1(s, 1H), 8.4(m, 1H), 8.7(m, 1H), 9.1(m, 2H), 10.6 (br s, 1H), 68 453.2 455.2 12.17,11.81(s, 1H), 10.35, 9.99(s, 1H), 9.13, 9.00(s, 1H), 8.52(s, 1H),7.99-7.69 (m, 5H), 7.32-7.27(m, 2H), 6.93-6,59 (m, 4H), 5.23(s, 2H),3.22(q, 2H), 1.13(t, 3H) 69 407.3 409.2 (MeOH-d₄, HCl salt)): 8.62(s,1H), 7.96-7.93(m, 2H), 7.59(s, 1H), 6.67(s, 1H), 5.81(s, 1H), 3.45,3.39(s, 3H), 3.36(q, 2H), 3.28, 3.20(s, 3H), 1.23(t, 3H) 70 — — 1.15(t,3H), 1.35(t, 3H), 3.25(q, 2H), 4.3(q, 2H), 7.1(br s, 1H), 7.85(s, 1H),8.05(m, 1H), 8.2(s, 1H), 8.3(s, 1H), 8.8 (m, 1H), 8.85(d, 1H), 9.25(s,1H), 9.65 (s, 1H), 10.7(br s, 1H), 71 416.2 418.2 0.84(m, 2H) 1.14(m,5H) 2.55(s, 3H) 2.91(m, 1H) 3.26(q, 2H), 6.59(s, 1H) 6.65(s, 1H) 6.69(s,1H) 7.65(s, 1H) 7.81(m, 1H) 7.97(s, 1H), 8.07(s, 1H) 9.07(s, 1H)11.59(s, 1H) 72 — — 1.1(t, 3H), 3.2(q, 2H), 7.1(br s, 1H), 7.8(s, 1H),8.0(m, 1H), 8.2(s, 1H), 8.25 (s, 1H), 8.7(m, 1H), 8.8(m, 1H), 9.2(s,1H), 9.6(s, 1H), 10.7(br s, 1H), 73 448.2 450.2 (CD₃OD): 1.18-1.26(m,9H), 3.27(s, 3H), 3.36(q, 2H), 4.21(s, 2H), 6.65-6.68 (m, 1H),6.90-6.94(m, 1H), 6.98-7.01 (m, 1H), 7.78-7.84(m, 2H), 7.93-7.96 (m,1H), 8.09-8.11(m, 1H), 8.74-8.76 (m, 1H) 74 434.3 436.3 (CD₃OD):1.21-1.27(m, 9H), 3.36(q, 2H), 4.17(s, 2H), 6.65-6.68(m, 1H),6.95-6.99(m, 1H), 7.00-7.03(m, 1H), 7.79-7.82(m, 1H), 7.89(d, 1H),7.94-7.96 (m, 1H), 8.09-8.11(m, 1H), 8.73- 8.76(m, 1H) 75 — — 1.1(t,3H), 3.0(br s, 3H), 3.25(m, 5H), 7.0(br s, 1H), 7.75(m, 2H), 8.05(s,1H), 8.15(s, 1H), 8.45(m, 1H), 8.7(m, 1H), 9.1(s, 1H), 9.4(s, 1H),10.4(br s, 1H), 77 448.3 450.2 (CD₃OD): d 1.24(t, 3H), 1.27(d, 3H),1.47(d, 3H), 3.36(q, 2H), 3.37(s, 3H), 3.58-3.67(m, 1H), 5.21-5.28(m,1H), 6.68-6.71(m, 1H), 7.80(d, 1H), 7.85(s, 1H), 7.95-7.99(m, 2H),8.27(s, 1H), 8.38(d, 1H), 8.78-8.82(m, 1H). 78 448.3 450.3 (CD₃OD): d1.24(t, 3H), 1.31(d, 3H), 1.51(d, 3H), 3.38(q, 2H), 3.42(s, 3H),3.66-3.73(m, 1H), 5.44-5.51(m, 1H), 6.68-6.71(m, 1H), 7.94(d, 1H), 7.96-7.98(m, 1H), 8.03(s, 1H), 8.07(s, 1H), 8.32(s, 1H), 8.43(d, 1H),8.81-8.86(m, 1H). 79 434.3 436.2 (CD₃OD): d 1.24(t, 3H), 1.32(d, 3H),1.50(d, 3H), 3.37(q, 2H), 3.93-4.02(m, 1H), 5.14-5.22(m, 1H),6.67-6.71(m, 1H), 7.90(d, 1H), 7.95-7.98(m, 1H), 8.02(s, 1H), 8.04(s,1H), 8.32(s, 1H), 8.41(d, 1H), 8.81-8.85(m, 1H). 82 428.2 430.1 9.0(m,1H), 8.6(d, 1H), 8.4(m, 1H), 8.1-8.2(m, 2H), 8.0(m, 1H), 7.8(m, 1H),7.5(m, 2H), 6.6(s, 1H), 4.8(s, 1H), 2.55(s, 3H), 3.25(m, 2H), 2.1(s,3H), 1.1(t, 3H) 83 417.1 419.1 11.01(br. s, 1H); 9.10(d, 1H); 8.37, (s,1H); 8.19(s, 1H); 7.97(s, 1H); 7.78(br. s, 1H); 7.58(m, 1H); 7.08, (s,1H); 6.68 (m, 1H); 3.88(dd, 2H); 3.22(dq, 2H); 2.99(dd, 2H);, 1.91(ddd,2H); 1.85 (ddd, 2H); 1.11(t, 3H). 84 377.2 379.2 (MeOD-d₃): 8.72(br s,1H), 8.58(s, 1H), 8.40(s, 1H), 8.19(s, 1H), 7.95(s, 1H), 7.14(s, 1H),6.68(s, 1H), 3.60(s, 3H), 3.21(q, 2H), 1.24(t, 3H). 85 430.2 432.2(MeOD-d₃, salt): 8.64(d, 1H), 8.14(s, 1H), 8.00(s, 1H), 7.97(d, 1H),7.64(s, 1H), 6.66(dd, 1H), 6.51(s, 1H), 3.89(s, 3H), 3.48(s, 3H),3.37(q, 2H), 1.24(t, 3H) 87 360.1 362.1 MeOD-d₃, 1.24(t, 3H), 2.42(s,3H), 3.38 (q, 2H), 6.87(s, 1H), 7.94(s, 1H), 8.15 (m, 2H), 8.85(d, 1H),8.98(d, 1H), 9.30 (s, 1H) 88 388 390 9.27(s, 2H). 9.20(S, 1H), 8.27(s,1H). 8.10(m, 1H), 7.94(s, H), 7.92(d, 1H), 6.95(d, 1H), 4.10(s, 3H),3.25(m, 2H), 1.11(t, 3H) 89 386.9 389.2 (CD₃OD) 8.92-6.96(m, 9ArH),3.99(s, 3H), 3.36(q, 2H), 1.24(t, 3H) 90 457.1 459.2 — 91 429.2 431.2(CD₃OD): 8.97(s, 1H); 8.89(d, 1H); 8.49(d, 1H); 8.37(m, 2H); 8.22(ddd,1H); 7.93(d, 1H); 7.64(dd, 1H); 3.38(q, 2H);2.91(m, 1H); 1.25(t, H):0.88(m, 2H); 0.67(m, 2H). 92 360.13 362.19 1.15(t, 3H), 3.25(m, 2H),3.9(s, 3H), 7.15(m, 1H), 7.65(m, 1H), 7.8(s, 1H), 8.0(s, 1H), 8.2(m,1H), 8.3(m, 1H), 8.65(m, 1H), 9.0(m, 2H), 10.3(br s, 1H) 93 371 3731.12(t, 3H), 3.25(m, 2H), 4.2(bs, 2H), 7.0.2-7.25(m, 1H), 7.5(m, 1H),7.81(m, 1H), 8.08(t, 1H), 8.22(m, 1H), 8.61-8.48(m, 2H), 8.4(d, 1H),8.46(s, 1H). 94 430 432 0.92(d, 6H), 1.12(m, 3H), 2.23(m. 1H), 2.83(d,2H), 3.35(m, 2H), 7.5(m, 1H), 7.61(bs, 1H), 7.89 (s, 1H), 8.1(rn, 1H),8.4(s, 1H), 8.58(m, 1H), 8.78(bs, 1H), 8.3(d, 1H). 95 431.03 433.2(CD₃OD) 1.2(7, 3H), 3.3(q, 2H), 3.8 (m, 2H), 4.6(m, 2H), 7.4(m, 1H), 7.8(m, 1H), 8.0(s, 1H), 8.3(m, 2H), 8.5(m, 1H), 8.7(m, 2H), 9.1(s, 1H) 96507.2 509.2 (CD₃OD): 8.9(d, 1H), 8.55(d, 1H), 8.4(s, 1H), 8.3(m, 1H),8.0(s, 1H), 7.7(m, 1H), 7.3(t, 1H), 7.0(s, 2H), 6.85(d, 1H), 6.7(d, 2H),5.5(s, 2H), 3.7(s, 3H), 3.3(q, 2H), 2.5(s, 3H), 1.25(t, 3H) 97 401 4039.1(s, 1H), 8.6(d, 2H), 8.3(m, 1H), 8.1 (s, 1H), 7.9(s, 1H), 7.8(s, 1H)7.5(m, 1H), 7.0(d, 1H), 4.3(m, 2H), 3.3(m, 2H), 1.4(t, 3H), 1.1(t, 3H).98 497.03 499.18 , 1.16(t, 3H) 3.25(q, 2H) 4.44(d, 2H) 7.17(t, 2H)7.38(t, 2H)7.53(t, 1H) 7.79(m, 1H) 7.87(s, 1H) 8.10(t, 1H) 8.32(s, 1H)8.51(s, 1H) 8.57(d, 1H) 8.77(s, 1H) 8.82(d, 1H) 8.94(t, 1H) 11.10(br s,1H) 99 432 434 — 100 418.25 420.15 1.1(t, 3H), 3.2(m, 2H), 3.95(s, 3H),4.1 (s, 2H), 7.2(br s, 1H), 7.25(brs, 1H), 7.9 (s, 1H), 8.2(m, 1H),8.25(s, 1H), 8.7(d, 1H), 9.05(s, 2H), 10.4(br s, 1H) 101 431 433 8.65(d,1H), 8.28(s, 1H), 8.24(s, 1H), 7.98(d, 1H), 7.78(d, 1H), 7.38(m, 1H),6.93(s, 1H), 6.89(dd, 1H), 4.51(q, 2H), 3.63(s, 3H), 3.35(q, 2H),1.55(t, 3H), 1.22(t, 3H) 102 375 377 8.86(d, 1H), 8.69(m, 1H), 8.52(d,1H), 8.16(m, 2H), 7.79(m, 2H), 7.56(m, 1H), 7.50(m, 1H), 3.55(m, 2H)1.23, (t, 3H) 103 430 432.1 8.87(br. s, 1H); 8.81(d, 1H); 8.66(br. s.,1H); 8.49(s, 1H); 8.39(br. s., 1H); 8.25 (d, 1H); 8.09(ddd, 1H); 7.87(d,1H); 7.52(dd, 1H); 5.3(very br. s, 5 H); 4.29 (q, 2H); 2.85(m, 1H);1.31(t, 3H); 0.72 (m, 2H); 0.63(m, 104 417.19 419.14 1.1(t, 3H), 3.2(q,2H), 3.45(s, 3H), 4.1 (s, 3H), 6.7(dd, 1H), 6.85(d, 1H), 7.15 (br s,1H), 7.35(br s, 1H), 7.8(d, 1H), 7.95(s, 1H), 8.2(s, 1H), 8.4(br s, 1H),8.7(d, 1H), 10.5(br s, 1H) 105 406 408 8.97(br. s, 2H); 8.60(d, 1H);7.99(br. s., 1H); 7.96(m, 1H); 7.81(br. s., 1H); 7.57(m, 1H); 3.98(s,3H); 3.25(m, 2H); 1.11(t, 3H). 106 508.2 510.2 1.1(t, 3H), 2.4(s, 3H),3.2(q, 2H), 4.1 (s, 3H), 5.4(s, 2H), 6.65(s, 1H), 6.75(s, 1H), 7.15(brs, 1H), 7.3(m, 2H), 7.35 (m, 1H), 7.8(m, 1H), 7.95(s, 1H), 8.25 (s, 1H),8.35(br s, 1H), 8.5(m, 1H), 8.75 (m, 1H), 10.5(br s, 1H) 107 495.2 497.28.8(m, 1H), 8.2(m, 1H), 7.9(s, 1H), 7.8(m, 1H), 7.4(m, 2H), 7.35(d, 2H),7.25(d, 2H), 6.7-6.8(m, 2H), 5.3(2, 2H), 4.0(m, 1H), 3.4(q, 2H), 2.4(s,3H), 1.1(t, 3H) 108 417 419 9.12(br. s, 1H); 8.60(d, 1H); 8.39(m, 1H);8.36(s, 1H); 8.25(s, 1H); 7.89(s, 1H); 7.70(dd, 1H); 7.41(m, 1H); 4.13(s, 3H); 3.98(s, 3H); 3.26(m, 2H); 1.15 (t, 3H). 109 358.3 360.1 (CD₃OD)9.61(d, 1H), 9.22(d, 1H), 8.83-8.79(m, 3H), 8.65(d, 1H), 8.47(d, 1H),8.02(dd, 1H), 8.00(s, 1H), 3.37(q, 2H), 1.24(t, 3H) 110 388.3 390.2(CDCl₃) 14.05(br s, 1H), 12.85(br s, 1H), 8.37(t, 1H), 7.97(d, 1H),7.88(d, 1H), 7.79-7.74(m, 2H), 7.63(dd, 1H), 7.46(d, 1H), 6.62(dd, 1H),5.75(br s, 1H), 3.45-3.40(m, 2H), 1.27(t, 3H) 111 492.3 494.1 10.3(s,1H), 8.9(d, 1H), 8.6(m, 1H), 8.5(d, 1H), 8.2(s, 1H), 8.05(t, 1H),7.8-7.9(m, 2H), 7.5(m, 2H), 7.4(d, 1H), 7.3(m, 1H), 6.7(s, 1H), 6.6(s,1H), 3.3(q, 2H), 1.9(d, 3H), 1.1-1.2(t, 3H). 112 475.2 477.2 10.62(s,1H); 8.74(d, 1H); 8.65(s, 1H); 8.40(s, 1H); 8.28(s, 1H); 8.23(s, 1H);7.87(s, 1H); 7.43(s, 1H); 7.32(m, 2H); 5.52-4.41(br. s, 3H); 4.10(s,3H); 3.24 (dt, 2H); 1.41(s, 9H); 1.13(t, 3H). 113 494.2 496.2 (CD₃OD)9.06(s, 1H); 8.93(d, 1H); 8.71 (d, 1H); 8.50(m, 2H); 8.39(s, 1H); 8.00(s, 1H); 7.87(dd, 1H); 7.42(d, 2H); 7.35 (dd, 2H); 7.25(dd, 1H); 5.27(q,1H); 4.41(q, 2H); 1.62(d, 3H); 1.42(t, 3H) 114 370.2 372.2 12.09 &12.74(s, 1H), 10.25 & 9.94(s, 1H), 9.12 & 8.94(s, 1H), 8.35-6.58(m, 9H),3.24(m, 2H), 1.13(t, 3H) 115 442.1 444.3 (CD₃OD) 8.65(d, 1H), 7.94(s,1H), 7.91 (d, 1H), 7.72(d, 2H), 7.66(s, 1H), 7.40 (d, 2H), 6.63(dd, 1H),4.52(s, 2H), 3.40 (t, 2H), 3.35(q, 2H), 2.47(t, 2H), 2.09- 2.03(m, 2H),1.24(t, 3H) 116 382 384 — 117 415 417 9.17(br. s, 1H); 9.0(m, 1H);8.98(d, 1H); 8.72(d, 1H); 8.55(m, 1H); 8.38(s, 1H); 7.94(s, 1H); 7.86(d,1H); 7.79(m, 1H); 3.97(s, 3H); 3.27(m, 2H); 1.15(t, 3H). 118 401 403 —119 403.3 405.2 (CD₃OD): 8.78(s, 1H), 8.67(d, 1H), 8.37(d, 1H), 8.24(d,1H), 8.22(s, 1H), 8.04(d, 1H), 7.91(s, 1H), 7.67(dd, 1H), 7.40(dd, 1H),4.22(s, 3H), 3.34(q, 2H), 1.23(t, 3H) 120 434.32 436.23 1.1(t, 3H),2.8(s, 6H), 3.2(m, 2H), 3.4 (s, 3H), 4.6(s, 2H), 6.6(d, 1H), 6.8(s, 1H),7.2(br s, 1H), 7.6(s, 1H), 7.8(d, 1H), 7.9(s, 1H), 7.95(s, 1H), 10.0(brs, 1H), 10.2(br s, 1H) 121 414 416 (CD₃OD): 9.40(br. s, 1H); 9.07(d,1H); 8.98(d, 1H); 8.91(d, 1H); 8.80(s, 1H); 8.60(s, 1H); 8.24(dd, 1H);8.11(d, 1H); 7.84(dd, 1H); 3.35(m, 2H); 3.01 (s, 3H); 1.25(t, 3H). 122415 417 — 123 435.28 437.26 1.3(t, 3H), 2.8(s, 6H), 3.5(s, 3H), 4.2 (q,2H), 4.6(s, 2H), 6.6(dd, 1H), 6.7(s, 1H), 7.7(s, 1H), 7.8(d, 1H), 8.0(m,2H), 10.1(br s, 1H), 11.7(br s, 1H) 124 431.2 433.2 9.28(s, 1H); 9.08(d,1H); 8.8-7.4(v. broad s, 4H); 8.67(s, 1H); 8.53(s, 1H); 8.46(d, 1H);8.05(d, 1H); 7.59(dd, 1H); 4.33(q, 2H); 2.88(m, 1H); 2.35(s, 6H);1.34(t, 3H); 0.76(m, 2H); 0.61(m, 2H). 125 447.4 — 9.10(s, 1H); 8.60(d,1H); 8.47(m, 2H); 7.95(s, 1H); 7.83(s, 1H); 7.12(d, 1H); 5.2-3.6(br. m,7H); 2.86(M, 1H); 1.30 (t, 3H); 0.75(m, 2H); 0.64(m, 2H) 126 439.2 441.2(CDCl₃) 13.89(br s, 1H), 12.89(br s, 1H), 8.28(d, 1H), 8.25(d, 1H),7.96(d, 1H), 7.74(s, 1H), 7.69-7.43(m, 6H), 7.40(s, 1H), 6.64(dd, 1H),6.11(br s, 1H), 3.46-3.40(m, 2H), 1.27(t, 3H) 127 418.2 420.2 (CD₃OD)9.72(d, 1H), 8.87(d, 1H), 8.82(d, 1H), 8.11(d, 1H), 8.09(d, 1H), 7.85(d,1H), 7.39(d, 1H), 7.36(d, 1H), 4.43(q, 2H), 3.35(q, 2H), 1.44(t, 3H),1.24(t, 3H) 128 449.8 452.1 (CD₃OD) 9.21(d, 1H), 8.83(ddd, 1H), 8.81(dd,1H), 8.68(d, 1H), 8.26(d, 1H), 8.18(d, 1H), 8.07(dd, 1H), 8.05(d, 1H),7.50(dd, 1H), 3.36(q, 2H), 3.34(s, 3H), 1.23(t, 3H) 129 — — 9.31(s, 1H);9.08(d, 2H); 8.63(s, 1H); 8.43(d, 1H); 8.02(d, 1H); 7.89(s, 1H); 7.57(t,1H); 8.8-6.6(very br. s, 4H); 4.31(q, 2H); 2.32(s, 6H); 1.42(s, 9H);1.33(t, 3H). 130 495.4 497.2 9.07(d, 2H); 8.73(d, 1H); 8.56(s, 1H);8.44(d, 1H); 8.03(d, 1H); 7.57(t, 3H); 7.44(d, 2H); 7.36(dd, 2H);7.26(dd, 1H); 6.95-5.90(very broad s., 5H); 5.18 (dt, 1H); 4.32(q, 2H);2.32(s, 6H); 1.53 (d, 3H); 1.33(t, 3H). 131 432 434 (CD₃OD) 1.08(d, 6H),1.43(t, 3H), 2.33(m, 1H), 2.91(d, 2H), 4.45(q, 2H), 7.53(t, 1H), 8.08(s,1H), 8.79(s, 1H) <8.94(s, 1H), 9.05(d, 2H), 9.5(s, 1H). 132 514.23516.23 8.84(d, 1H), 8.81-8.83(m, 1H), 8.35(s, 1H), 8.06(dd, 1H),7.90(dd, 1H), 7.80 (d, 1H), 6.80(br s, 1H), 6.70(d, 1H), 4.30(q, 2H),3.42-3.54(m, 4H), 3.48(s, 3H), 3.12-3.17(m, 4H), 2.81(d, 3H), 1.32(t,3H)ppm 133 501.33 503.26 — 134 521.6 523.2 (CD₃OD) 8.82(s, 1H),m 8.46(d,1H), 8.30(s, 1H), 8.13(dd, 1H), 7.90(s, 1H), 7.55(dd, 1H), 7.28(dd, 1H),6.86-6.77 (m, 4H), 6.74(s, 1H), 3.77(s, 3H), 3.36 (q, 2H), 2.41(br s,3H), 1.97(d, 3H), 1.24(t, 3H) 135 470.3 472.5 (CD₃OD) 8.85(br s, 1H),8.45(d, 1H), 8.34(dd, 1H), 8/26(dd, 1H), 8.13(ddd, 1H), 7.96(dd, 1H),7.56(dd, 1H), 7.43 (dd, 1H), 7.29 & 7.20(s, 1H), 5.49(m, 1H),3.66-3.25(m, 4H), 3.38(q, 2H), 2.94(2s, 3H), 2.52(m, 1H), 2.38(m, 1H),2.15(m, 1H) 136 521.3 523.3 (CD₃OD) 8.81(d, 1H), 8.43(d, 1H), 8.27(s,1H), 8.11(ddd, 1H), 7.88(s, 1H), 7.54(dd, 1H), 7.28(dd, 1H), 6.87 (d,1H), 6.84(d, 1H), 6.81(s, 1H), 4.42 (q, 2H), 3.78(s, 3H), 2.50(br s,3H), 2.00(d, 3H), 1.41(t, 3H) 137 522.6 524.2 (CD₃OD) 8.90(d, 1H),8.81(d, 1H), 8.49(dd, 1H), 8.41(s, 1H), 8.06(s, 1H), 7.84(dd, 1H),7.29(dd, 1H), 6.99(br s, 1H), 6.92(s, 1H), 6.87(d, 1H), 6.84(d, 1H),6.81(s, 1H), 4.42(q, 2H), 3.78(s, 3H), 2.50(br s, 3H), 2.00(d, 3H), 1.41(t, 3H) 138 525 527 1.2(t.3H). 1.5(d, 3H), 3.73(s, 3H), 4.3(q, 2H),5.13(m, 1H), 6.8(d, 1H), 7.0(m, 2H), 7.24(t, 1H), 7.53(t, 1H), 7.93(s,1H), 8.24(s, 1H), 8.32(m, 2H), 8.4(s, 1H), 9.08(s, 1H), 11.79(bs, 1H),12.18(s, 1H). 139 522.5 524.2 (CD₃OD): 8.86(d, 1H), 8.74(d, 1H),8.41(dd, 1H), 8.35(s, 1H), 7.99(s, 1H), 7.78(dd, 1H), 7.28(dd, 1H),6.85(d, 1H), 6.83(d, 1H), 6.80(s, 2H),m 6.76(s, 1H), 4.41(q, 2H),3.77(s, 3H), 2.41(br s, 3H), 1.97(d, 3H), 1.41(t, 3H) 140 499 501 — 141425.3 427.2 (CD₃OD) 8.8(d, 1H), 8.35(d, 1H), 8.2(s, 1H), 8.1(t, 1H),8.0(s, 1H), 7.9(d, 1H), 7.8(s, 1H), 7.65-7.7(dd, 1H), 7.5(t, 1H),7.49(d, 1H), 4.6(s, 2H), 4.45(s, 1H), 3.4(q, 2H), 3.2(s, 3H), 3.15(s,1H), 1.2(t, 3H) 142 426.3 428.2 (CD₃OD): 8.8(d, 1H), 8.6(d, 1H), 8.3(m,2H), 8.1(s, 1H), 8.0(d, 1H), 7.9(s, 1H), 7.7(d, 1H), 4.6(s, 2H), 4.45(s,1H), 4.4- 4.5(q, 2H), 3.3(s, 3H), 3.15(s, 1H), 1.4(t, 3H) 143 498 500 —144 497 499 (CD₃OD) 1.42(t, 3H), 1.84(d.3H), 4.49(q, 2H), 6.43(q, 1H).7.58(t, 1H), 8.03(t, 1H), 8.08(s, 1H), 8.23(d, 1H), 8.67(t, 1H), 8.73(s,1H), 8.39(d, 2H), 8.88(d, 2H), 9.06(s, 2H). 145 457 459 (CD₃OD) 1.4(t,3H), 3.48(d, 4H), 3.99(s, 4H), 4.41(s, 2H), 7.7(d, 1H), 8.07(s, 1H)8.05(m, 3H), 8.73(s, 1H), 8.9(s, 1H), 9.12(s, 1H). 146 — 502.21 (CD₃OD)8.89(s, 1H), 8.49(d, 1H), 8.45 (s, 1H), 8.22(d, 1H), 8.11(d, 1H), 8.06(s, 1H), 7.47(br d, 1H), 7.36(br s, 1H), 3.91(s, 3H), 3.68-3.89(br m,8H), 3.38 (q, 2H), 1.25(t, 3H)ppm 147 — 487.2 (CD₃OD) 8.99(s, 1H),8.54(d, 1H), 8.46 (s, 1H), 8.27(d, 1H), 8.01(s, 1H), 7.85 (br s, 1H),6.97(br s, 1H), 6.91(br s, 1H), 4.47(q, 2H), 3.66-3.69(m, 5H),3.59-3.62(m, 2H), 2.01-2.06(m, 2H), 1.96-2.00(m, 2H), 1.43(t, 3H) ppm148 375 377 (CD₃OD): 9.02(t, 2H), 8.98(s, 2H), 8.82(d, 1H), 8.05(d, 1H),7.54(t, 1H), 4.48(q, 2H), 1.44(t, 3H) 149 — 486.22 (CD₃OD) 8.98(s, 1H),8.44(m, 1H), 8.38(br s, 1H), 8.19(br d, 1H), 8.02(br s, 1H), 7.98(br s,1H), 7.15(br s, 1H), 7.13(br s, 1H), 3.79(br s, 3H), 3.67(m, 2H),3.61(m, 2H), 3.37(q, 2H), 2.05(m, 2H), 2.00(m, 2H), 1.25(t, 3H) p 150494.3 496.2 (CD₃OD) 9.0(d, 2H), 8.8(s, 1H), 8.6(d, 1H), 8.2(t, 1H),7.95(s, 1H), 7.8(d, 1H), 7.65(t, 1H), 7.5(t, 1H), 6.9(s, 1H), 6.6(s,1H), 6.1(m, 1H), 4.4(q, 2H), 2.7(s, 3H), 2.05(d, 3H), 1.4(t, 3H) 151493.4 495.2 (CD₃OD) 8.95(d, 2H), 8.6(s, 1H), 8.5(d, 1H), 8.1(t, 1H),7.8(s, 1H), 7.7(d, 1H), 7.5(t, 1H), 7.4(1, 1H), 6.8(s, 1H), 6.6(s, 1H),6.0(m, 1H), 3.35(q, 2H), 2.6(s, 3H), 2.0(d, 3H), 1.2(t, 3H) 152 — 462.21(CD₃OD) 8.90(d, 1H), 8.81(d, 1H), 8.49(m, 1H), 8.39(d, 1H), 8.04(d, 1H),7.85(m, 1H), 7.02(br s, 1H), 6.90(d, 1H), 4.82(m, 1H, underneath waterpeak), 4.42(q, 2H), 4.29(m, 1H), 3.72 (m, 1H), 3.35(s, 3H), 2.65 &2.90(s, 3H), 1 153 504.3 506.3 12.14(s, 1H); 11.11(s, 1H);9.59(s, 1H);9.08(d, 2H); 8.38(s, 1H); 8.33(d, 1H); 8.22(s, 1H); 7.95(d, 1H);7.56(dd,1H); 4.32(q, 2H); 4.12(br. s, 4H); 3.62 (br. s, 4H); 2.46(br. s, 2H);1.31(dd, 2H); 1.22(t, 3H). 154 474.3 476.3 10.31(s, 1H); 9.09(d, 2H);8.79(s, 1H); 8.44(s, 1H); 8.42(s, 1H); 8.00(s, 1H); 7.68(t, 2H);7.7-6.6(br. s, 3H); 4.32(q, 2H); 3.55(m, 4H); 3.12(m, 4H); 2.34(s, 6H);1.32(t, 3H). 155 479.3 481.2 1.33(t, 3H) 2.36(s, 3H) 4.35(q, 2H) 5.60(s,2H) 6.84(s, 1H) 6.88(s, 1H) 7.68(t, 1H) 7.81(d, 2H) 7.99(s, 1H) 8.26(t,1H) 8.35(s, 1H) 8.78(d, 1H) 8.89(d, 3H) 11.75(br s, 2H) 156 — 461.22(CD₃OD) 8.83(m, 1H), 8.44(d, 1H), 8.25(d, 1H), 8.12(m, 1H), 7.88(d, 1H),7.54(m, 1H), 6.70(s, 1H), 6.68(s, 1H), 4.68(m, 1H), 4.32(m, 1H), 3.70(m,1H), 3.38(q, 2H), 3.35(s, 3H), 2.56(s, 3H), 1.60(d, 3H), 1.24(t, 3H) ppm157 486.3 488.3 (CD₃OD) 1.37(t, 3H) 1.57(m, 4H) 2.27(m, 1H) 2.82(s, 3H)3.41(t, 2H) 3.96(d, 2H) 4.29(d, 2H) 4.43(q, 2H) 7.27(s, 1H) 7.50(s, 1H)7.90(t, 1H) 8.17(s, 1H) 8.55(s, 1H) 8.659(t, 1H) 8.95(d, 1H) 9.09(d, 1H)158 474.3 476.3 (CD₃OD) 1.08(d, 6H) 1.42(t3H) 2.76(s, 3H) 3.57(m, 1H)2.82(t, 2H) 4.42(m, 4H) 6.98(s, 1H) 7.05(s, 1H) 7.86(t, 1H) 8.09(s, 1H)8.41(s, 1H) 8.51(t, 1H) 8.82(d, 1H) 8.91(d, 1H) 159 458 460 (CD₃OD)1.43(t, 3H), 3.48(bs, 24H), 3.99(bs, 4H), 4.48(1, 2H), 4.63(s, 2H),7.55(t, 1H), 7.71(d, 1H), 8.1(s, 1H), 8.33(d, 1H), 8.9(1H), 9.03(d, 2H),9.13(s.1H). 160 457 459 (CD₃OD) 1.35(t, 3H), 3.3-3.5(m, 6H), 3.99(bs,4H), 4.62(s, 2H), 7.52(t, 1H), 7.7(d, 1H), 8.08(s, 1H), 8.32(d, 1H),8.88(s, 1H), 9.05(d, 2H) 9.1(s, 1H). 161 446.28 448.2 1.2(t, 3H), 3.2(m,2H), 3.3(br s, 4H), 3.9(br s, 4H), 4.7(s, 2H), 7.7(s, 1H), 7.8(br s,1H), 7.95(m, 1H), 8.1(s, 1H), 8.25(s, 1H), 8.7(m, 1H), 8.8(m, 1H),9.2(s, 1H), 10.6(br s, 1H) 162 550.3 552.3 12.32(s, 1H); 11.18(s, 1H);9.08(d, 2H); 8.62(s, 1H); 8.39(s, 1H); 8.37(s, 1H); 7.98(s, 1H); 7.62(m,2H); 7.58 (dd, 1H); 7.48(m, 3H); 6.4-5.9(br. s, 3H); 4.38(s, 2H);4.33(q, 2H); 3.42(m, 4H); 3.15(m, 4H); 1.35(t, 3H). 163 501.3 503.3(CD₃OD) 9.1(d, 1H), 8.8(t, 1H), 8.5(d, 1H), 8.4(s, 1H), 8.3(s, 1H),8.2(t, 1H), 7.7(s, 1H), 7.5(s, 1H), 4.8(t, 2H), 4.4(q, 2H), 4.1(d, 2H),3.9(t, 2H), 3.75(d, 2H), 3.7(t, 2H), 3.4(m, 2H), 3.3(s, 2H), 2.85(s,3H), 2.0(s, 5H), 1.4(t, 3H) 164 500.4 502.3 (CD₃OD) 8.75(d, 1H), 8.3(d,1H), 8.2(s, 1H), 8.0-8.05(1, 1H), 7.8(s, 1H), 7.5(t, 1H), 6.8(s, 1H),6.7(s, 1H), 4.5-4.6(1, 2H), 4.0(brd s, 4H), 3.5-3.6(1, 4H), 3.4(q, 2H),3.3(t, 2H), 2.6(s, 3H), 1.2-1.3(1, 3H) 165 474 476 (CD₃OD) 9.04(d, 1H),8.71(d, 1H), 8.34(d, 1H), 8.23(dd, 1H), 7.94(d, 1H), 7.84(m, 1H),7.65(d, 1H), 7.57(m, 1H), 4.56(s, 2H), 3.98(t, 4H), 3.45(t, 4H), 3.37(q,2H), 1.24(t, 3H) 166 475 477 (CD₃OD): 9.07(d, 1H), 8.72(d, 1H), 8.49(d,1H), 8.28(dd, 1H), 8.04(d, 1H), 7.92(m, 1H), 7.69(d, 1H), 7.63(m, 1H),4.63(s, 2H), 4.47(q, 2H), 3.99(m, 4H), 3.44(m, 4H), 1.43(t, 3H) 167522.3 524.4 (CD₃OD) 8.94(d, 2H), 8.65(s, 1H), 7.85 (s, 1H), 7.44(dd,1H), 7.27(dd, 1H), 6.84(d, 2H), 6.80(s, 1H), 6.70(s, 1H), 6.64(s, 1H),3.77(s, 3H), 3.36(q, 2H), 2.39(br s, 3H), 1.96(d, 3H), 1.24(t, 3H) 168 —474.3 (CD₃OD) 1.45(t, 3H) 1.80(d, 3H) 2.69(m, 2H) 3.50(m, 2H) 3.97(m,4H) 4.49(q, 2H) 4.72(m, 1H)7.55(t, 1H) 7.71(d, 1H) 1.15(s, 1H) 8.33(d,1H) 8.91(s, 1H) 9.08(d, 2H) 9.17(s, 1H) 169 445.44 447.24 1.3(t, 3H),2.9(br s, 6H), 3.6(brs, 2H), 4.3(q, 2H), 4.6(m, 2H), 7.1(m, 1H), 7.6 (m,1H), 7.9(s, 1H), 8.2(m, 1H), 8.25 (s, 1H), 8.3(m, 1H), 8.6(d, 1H),8.7(d, 1H), 9.1(s, 1H), 9.7(br, s, !H) 170 444.43 446.22 1.2(t, 3H),2.9(br s, 6H), 3.25(m, 2H), 3.6(br s, 2H), 4.6(m, 2H), 7.1(m, 1H),7.4(br s, 1H), 7.6(m, 1H), 7.9(s, 1H), 8.1(br s, 1H), 8.2(s, 1H), 8.3(m,1H), 8.6(d, 1H), 8.7(d, 1H), 9.1(s, 1H), 9.8 (br s, 1H), 10.5(br s, 1H)171 460.2 462.2 (CD₃OD) 8.95(d, 1H), 8.86(d, 1H), 8.57(dt, 1H), 8.46(d,1H), 8.17(d, 1H), 7.93(t, 1H), 7.62(br s, 1H), 7.33(d, 1H), 5.14(m, 1H),4.42(q, 2H), 4.26(m, 1H), 3.75(dd, 1H), 3.36(s, 3H), 2.81(s, 3H),1.42(d, 3H), 1.30(t, 3H) ppm 172 485 487 (CD₃OD) 1.45-1.12(m, 3H),1.9(m, 1H), 2.1(m, 2H), 2.32(m, 1H), 3.5-3.3(m, 5H), 3.7(m, 4H),3.99(bs, 1H), 4.4(q, 2H), 4.57(bd, 1H), 7.58(d, 1H), 7.8(t, 1H), 8.03(s,1H), 8.32(d, 1H), 8.42(m, 2H), 8.75(d, 1H), 8.88(s, 1H) 9.1(s, 1H). 173484 486 (CD₃OD) 1.15(t, 3H), 1.4(t, 3H), 3.02(s, 2H), 3.6(m, 2H),3.68(m, 2H), 3.95(s, 2H), 4.4(m, 2H), 4.61(s, 2H), 7.8(m, 2H), 8.08(s,1H), 8.48(m, 3H), 8.78(d, 1H), 8.9(d, 1H), 9.17(s, 1H). 174 503.2 505.2(CDCl₃) 8.94(d, 1H), 8.87(d, 1H), 8.15 (d, 1H), 8.11(d, 2H), 7.95(ddd,1H), 7.90(s, 1H), 7.70(d, 1H), 7.42(dd, 1H), 4.76(s, 2H), 4.46(q, 2H),3.82(t, 4H), 3.64(t, 4H), 3.40(s, 6H), 1.45(t, 3H) 175 593.4 595.310.85(s, 1H); 8.84(s, 1H); 8.72(s, 1H); 8.58(d, 1H); 8.52(s, 1H);8.30(d, 1H); 8.08(s, 1H); 7.92(d, aH); 7.44(d, 2H); 7.34(dd, 2H);7.24(t, 1H); 6.05-4.9(br. s); 5.21(dq, 1H); 4.78(d, 2H); 4.31(q, 2H);3.58(d, 2H); 3.52( 176 543.5 545.3 11.76(s, 1H);9.59(s, 1H); 8.89(d,1H); 8.78(s, 1H); 8.65(s, 1H); 8.40(s, 1H); 8.05(d, 1H); 7.9-6.2(br. s,2H); 4.87(d, 2H); 4.32(q, 2H); 3.96(dd, 2H); 3.68 (dd, 2H); 3.58(m,4H);3.20(m, 2H); 2.94(d, 3H); 1.98(m, 2H); 1.88 177 542.5 544.3 11.12(s,1H); 10.84(s, 1H); 9.08(s, 1H); 8.87(d, 1H); 8.66(s, 1H); 8.41(s, 1H);8.01(s, 1H); 7.96(d, 1H); 7.58(s, 1H); 6.3-4.6(br. s, 6H); 4.82(d, 2H);3.96(dd, 2H); 3.58(m, 6H); 3.26(m, 2H); 3.15(m, 2H); 2.84(d, 3H); 1.96(178 470.4 472.3 9.05(d, 2H); 8.54(s, 1H); 7.89(s, 1H); 8.01(s, 1H);7.78(d, 1H); 7.55(t, 1H); 7.05(d, 1H); 5.5-4.2(br. s, 1H); 4.33(q, 2H);3.50(dd, 2H); 3.36(dd, 2H); 3.12 (s, 3H); 2.85(s, 3H); 1.33(t, 3H). 179415.4 417.3 (CD₃OD) 9.54(d, 1H), 9.21(m, 1H), 9.15(s, 1H), 8.97(d, 1H),8.92(d, 1H), 8.83(d, 1H), 8.28(dd, 1H), 8.20(d, 1H), 7.69(m, 1H),4.62(s, 2H), 4.48(q, 2H), 3.00(s, 6H), 1.44(t, 3H) ppm 180 414.4 416.3(CD₃OD) 9.54(d, 1H), 9.22(m, 1H), 9.05(s, 1H), 8.97(d, 1H), 8.93(d, 1H),8.79(d, 1H), 8.28(dd, 1H), 8.17(d, 1H), 7.62(m, 1H), 4.59(s, 2H),3.39(q, 2H), 2.99(s, 6H), 1.25(t, 3H) ppm 181 513 515 (CD₃OD): 9.14(d,1H), 9.06(d, 1H), 8.85(t, 1H), 8.67(t, 1H), 8.46(d, 1H), 8.37(d, 1H)8.11(m, 1H), 7.97(d, 1H), 7.55(m, 1H), 4.07(brs, 2H), 3.88(t, 4H),3.71(brs, 2H), 3.48(t, 4H), 3.36(q, 2H), 1.24(t, 3H) 182 477.4 479.370.9(d, 6H), 1.3(t, 3H), 2.1(m, 1H), 2.9 (s, 6H), 3.75(d, 2H), 4.3(q,2H), 4.6(s, 2H), 6.6(dt, 1H), 6.7(d, 1H), 7.7(s, 1H), 7.8(d, 1H),7.95(s, 1H), 8.010.2 (br s, 1H)(s, 1H), 183 476.42 478.41 0.9(d, 6H),1.1(t, 3H), 2.1(m, 1H), 2.9 (s, 6H), 3.2(m, 2H), 3.8(d, 2H), 4.6(s, 2H),6.6(dt, 1H), 6.7(d, 1H), 7.3(br s, 1H), 7.7(s, 1H), 7.8(d, 1H), 7.95(s,1H), 8.0(s, 1H), 10.2(br s, 1H) 184 514 516 — 185 470.4 472.2 (CD₃OD)1.25(t, 3H) 1.78(d, 3H) 3.30(m, 2H) 3.35(q, 2H) 3.50(m, 2H) 3.93 (m, 4H)4.73(q, 1H) 7.72(t, 1H) 7.45(d, 1H) 8.01(s, 1H) 8.27(t, 1H) 8.35(m, 2H)8.52(d, 1H) 8.91(d, 1H) 9.18(s, 1H) 186 498.4 500.3 (CD₃OD) 1.16(m, 3H)1.26(m, 6H) 1.80(d, 3H) 2.82(t, 2H) 3.20(d, 1H) 3.35(q, 2H) 3.72(d, 1H)3.91(m, 1H) 4.04(m, 1H) 4.68(q, 1H) 7.65(t, 1H) 7.71(d, 1H) 8.01(s, 1H)8.22(t, 1H) 8.35(m, 2H) 8.49(d, 1H) 8.89(d, 1H) 9.18(s, 1H) 187 499.5501.3 (CD₃OD) 1.16(m, 3H) 1.29(d, 3H) 1.41(t, 3H) 1.79(d, 3H) 2.82(t,2H) 3.20(d, 1H) 3.74(d, 1H) 3.92(m, 1H) 4.04(m, 1H) 4.43(q, 2H) 4.69(q,1H) 7.70(d, 1H) 7.87(t, 1H) 8.11(s, 1H) 8.35(d, 1H) 8.46(m, 2H) 8.75(d,1H) 8.92(d, 1H) 9.34(s, 1H) 188 486 488 (CD₃OD): 8.91(m, 1H), 8.65(m,1H), 8.47(m, 1H), 8.31(m, 2H), 8.29(m, 1H), 7.96(m, 1H) 7.73(m, 1H),7.19(m, 1H), 4.08(m, 2H), 3.90(m, 2H), 3.72(m, 4H), 3.66(m, 4H), 3.37(m,2H), 1.24(t, 3H) 189 487 489 (CD₃OD): 8.89(d, 1H), 8.69(d, 1H), 8.61(d,1H), 8.41(t, 1H), 8.32(d, 1H), 8.20(dd, 1H) 7.95(d, 1H), 7.78(t, 1H),7.10(d, 1H), 4.42(q, 2H), 4.09(m, 2H), 3.86(m, 2H), 3.70(m, 4H), 3.33(m,4H), 1.24(t, 3H) 190 388.38 390.19 1.2(t, 3H), 3.3(m, 2H), 3.5(s, 3H),6.6 (dd, 1H), 6.7(d, 1H), 7.6(t, 1H), 7.8(d, 1H), 7.95(br s, 1H), 8.0(s,1H), 8.6(s, 1H), 9.05(d, 2H) 191 359.3 361.2 — 192 446.4 448.3 — 193474.2 476.4 (CD₃OD) 9.14(s, 1H), 9.08(d, 2H), 8.91 (s, 1H), 8.39(d, 1H),8.14(s, 1H), 7.78 (s, 1H), 7.55(dd, 1H), 4.72(s, 2H), 4.48 (q, 2H),3.81(t, 2H), 3.56(t, 2 H), 3.46 (q, 2H), 3.41(s, 3H), 1.44(t, 3H), 1.43(t, 3H) 194 486.1 488.1 (CDCl₃) 12.31(br s, 1H), 8.95(s, 1H), 8.93(d,2H), 8.58(s, 1H), 8.05(s, 1H), 8.01(d, 1H), 7.50(d, 1H), 7.24(dd, 1H),4.46(q, 2H), 3.78(m, 2H), 3.72(s, 2H), 2.78(d, 2H), 1.91(dd, 2H),1.41(t, 3H), 1.17(d, 6H) 195 — — 11.5(br s, 1H), 9.19(br s, 1H), 8.97(s,1H), 8.88(d, 1H), 8.45(m, 1H), 8.40(s, 1H), 7.98(d, 1H), 7.77(d, 1H),7.60(d, 1H), 4.57(s, 2H), 4.47(br d, 2H), 4.32 (q, 2H), 3.90(br m, 4H),3.32(br s, 4H), 2.80(d, 6H), 1.34 197 460.2 462.2 (CD₃OD & CDCl₃):8.98(d, 2H), 8.85(d, 1H), 8.60(d, 1H), 8.16(dd, 1H), 7.86(d, 1H),7.67(d, 1H), 7.40(dd, 1H), 4.37(q, 2H), 3.81(s, 2H), 3.60(t, 2H),3.37(s, 3H), 2.74(t, 2H), 2.38(s, 3H), 1.41(t, 3H) 198 459.3 461.2(CD₃OD): 8.95(d, 2H), 8.83(s, 1H), 8.54(s, 1H), 8.15(d, 1H), 7.82(s,1H), 7.65(d, 1H), 7.39(dd, 1H), 3.79(s, 2H), 3.59(t, 2H), 3.36(q, 2H),3.35(s, 3H), 2.72(t, 2H), 2.36(s, 3H), 1.24(t, 3H) 199 488 490 — 200 487489 — 201 488 490 — 202 487 489 — 203 489 491 9.06(m, 4H), 8.50(d, 1H),7.98(d, 1H), 7.54(t, 1H), 4.79(t, 2H), 4.31(q, 2H), 4.01(m, 2H), 3.79(m,2H), 3.67(m, 2H), 3.56(m, 2H), 3.25(m, 2H) 1.33(t, 3H) 204 488 490(CD₃OD): 9.02(m, 4H), 8.75(s, 1H), 7.97(d, 1H), 7.52(m, 1H), 4.88(m,2H), 3.75-3.73(m, 10H), 3.35(m, 2H), 1.25(t, 3H) 205 400.1 402.1 1.31(t,3H) 2.70(s, 3H) 4.32(q, 2H) 7.55(t, 1H) 8.00(s, 1H) 8.09(d, 1H) 8.14(t,1H) 8.39(s, 1H) 8.44(d, 1H) 8.70(d, 1H) 8.81(d, 1H) 9.19(s, 1H) 206458.1 460 (CD₃OD) 9.41(d, 2H), 8.92(m, 1H), 8.80(d, 1H), 8.48(m, 2H),8.10(br s, 1H), 7.84(m, 1H), 4.76(s, 2H with water peak), 4.42(q, 2H),4.11(br m, 2H), 3.95(nr m, 2H), 3.71(br m, 2H), 3.45(br m, 2H), 1.42(t,3H) ppm. 207 457.2 459.1 (CD₃OD) 9.33(s, 2H), 8.89(d, 1H), 8.53 (d, 1H),8.44(d, 1H), 8.20(m, 1H), 8.04 (d, 1H), 7.63(m, 1H), 4.76(s, 2H, withwater peak), 4.12(br m, 2H), 3.94(br m, 2H), 3.71(br m, 2H), 3.44(br m,2H), 3.39(q, 2H), 1.25(t, 3H) ppm 208 391 393 — 209 441.1 443 (CD₃OD)1.43(t, 3H) 4.50(s, 2H) 4.89(s, 2H) 7.55(t, 1H) 8.10(d, 1H) 8.20(s, 1H)8.87(d, 1H) 9.01(s, 1H) 9.10(d, 2H) 9.30(s, 1H) 210 472.4 474.2 (CD₃OD)9.25(s, 1H), 9.02(d, 2H), 8.87 (d, 1H), 8.65(d, 1H), 8.18(s, 1H), 8.08(d, 1H), 7.54(dd, 1H), 4.88(s, 2H), 4.49 (q, 2H), 4.27(br s, 1H),3.68(m, 4H), 3.40(s, 3H), 2.32(m, 2H), 1.45(t, 3H) 211 471.2 473.1(CD₃OD) 9.16(s, 1H), 8.98(d, 2H), 8.76 (d, 1H), 8.48(d, 1H), 8.05(s,1H), 7.91 (d, 1H), 7.50(dd, 1H), 4.81(s, 2H), 4.27 (br s, 1H), 3.69(m,4H), 3.40(s, 3H), 3.38(q, 2H), 2.32(m, 2H), 1.26(t, 3H) 212 485.2 487.3(CD₃OD) 9.16(s, 1H), 9.03(d, 2H), 8.87 (s, 1H), 8.50(d, 1H), 8.14(s,1H), 7.92 (d, 1H), 7.54(dd, 1H), 4.75(s, 2H), 4.49 (q, 2H), 4.06(s, 2H),3.74(br s, 4H), 3.06(s, 3H), 1.45(t, 3H) 213 484.2 486.2 (CD₃OD) 9.16(s,1H), 9.01(d, 2H), 8.78 (s, 1H), 8.52(d, 1H), 8.07(s, 1H), 7.96 (d, 1H),7.52(dd, 1H), 4.77(s, 2H), 4.07 (s, 2H), 3.75(br s, 4H), 3.38(q, 2H),3.06(s, 3H), 1.26(t, 3H) 214 350.1 12.28(br. s, 1H); 11.77(br. s, 1H);9.73 (s, 1H); 9.08(d, 2H); 8.49(d, 1H); 8.37 (m, 1H); 8.08(d, 1H);7.94(m, 1H); 7.59 (t, 1H); 4.32(q, 2H); 2.30(s, 3H); 1.32 (t, 3H). 215502.4 504.1 (CD₃OD) 9.17(s, 1H), 9.02(d, 2H), 8.85 (s, 1H), 8.48(d, 1H),8.15(s, 1H), 7.90 (d, 1H), 7.53(dd, 1H), 4.81(d, 1H), 4.77 (d, 1H),4.48(q, 2H), 4.18(br s, 2H), 3.75(m, 4H), 3.47(s, 6H), 1.45(t, 3H) 216347.2 349.1 12.28(br. s, 1H); 10.22(br. s, 1H); 9.53 (s, 1H); 9.08(d,2H); 8.41(d, 1H); 8.29 (m, 1H); 7.98(d, 1H); 7.83(m, 1H); 7.57 (t, 1H);7.22(m, 1H); 3.26(dq, 2H); 2.31 (s, 3H); 1.15(t, 3H). 217 501.4 503.1(CD₃OD) 9.15(s, 1H), 9.03(d, 2H), 8.85 (s, 1H), 8.43(d, 1H), 8.10(s,1H), 7.83 (d, 1H), 7.53(dd, 1H), 4.78(d, 1H), 4.74 (d, 1H), 4.18(br s,2H), 3.74(m, 4H), 3.47(s, 6H), 3.38(q, 2H), 1.26(t, 3H) 218 456 458(CD₃OD) 1.24(t, 3H), 3.38(m, 2H), 3.57(bs, 4H), 3.99(bs, 4H), 4.63(s,2H), 7.68(m, 1H), 7.73(m, 1H), 8.02(s, 1H), 8.24(t, 1H), 8.48(m, 1H),8.49(d, 1H), 8.9(d, 1H), 9.13(s, 1H). 219 — — 12.25(s, 1H); 11.75(s,1H); 9.61(d, 1H); 9.07(d, 2H); 8.45(s, 1H); 8.11(s, 1H); 8.02(d, 1H);7.59(t, 1H); 4.31(q, 2H); 2.38(s, 3H); 2.29(s, 3H); 1.32(t, 3H). 220502.3 504.2 (CD₃OD) 9.10(d, 1H), 9.05(d, 2H), 8.91(d, 1H), 8.32(dd, 1H),8.11(d, 1H), 7.69(d, 1H), 7.55(dd, 1H), 4.73(d, 1H), 4.69(d, 1H),4.49(q, 2H), 4.17(br s, 2H), 3.70(m, 4H), 3.46(s, 6H), 1.44(t, 3H) 221501.3 503.2 (CD₃OD) 9.09(s, 1H), 9.05(d, 2H), 8.86 (s, 1H), 8.29(d, 1H),8.09(s, 1H), 7.67 (d, 1H), 7.54(dd, 1H), 4.72(d, 1H), 4.67 (d, 1H),4.17(br s, 2H), 3.71(m, 4H), 3.47(s, 6H), 3.39(q, 2H), 1.26(t, 3H) 222 —559 (CDCl₃) 12.29(br s, 1H), 8.94(s, 1H), 8.94(d, 2H), 8.60(s, 1H),8.04(s, 1H), 8.02(d, 1H), 7.50(d, 1H), 7.25(dd, 1H), 4.46(q, 2H),3.75(s, 2H), 3.50(m, 4H), 2.51(m, 4H), 1.47(s, 9H), 1.41(t, 3H) 223513.2 515.14 1.1(d, 6H), 1.3(t, 3H), 3.5(m, 4H), 3.7 (br s, 2H), 4.3(q,2H), 4.5(br s, 2H), 4.65(m, 1H), 7.5(t, 1H), 7.7(d, 1H), 8.0 (d, 1H),8.3(dd, 1H), 8.5(d, 1H), 9.0(d, 2H), 9.05(d, 1H) 224 457.207 459.207(CD₃OD) 9.54(s, 1H), 9.28(s, 1H), 9.22 (d, 1H), 8.97(d, 1H), 8.93(d,1H), 8.85 (br s, 1H), 8.27(t, 1H), 8.20(br s, 1H), 7.71(d, 1H), 4.63(s,2H), 4.48(q, 2H), 4.05(br s, 4H), 3.44(br m, 4H), 1.44(t, 3H) ppm 225472.2 474.49 (CD₃OD) 9.0(d, 1H), 8.95(m, 1H), 8.6(s, 1H), 8.5(s, 1H),8.4(s, 1H), 8.3(s, 1H), 7.9(s, 1H), 7.55(m, 1H), 4.5(s, 2H), 3.9(s, 2H),3.4(q, 2H), 3.0(s, 6H), 1.3(t, 3H). 226 562.3 564.2 (CD₃OD) 9.0(d, 1H),8.9(m, 1H), 8.6(s, 1H), 8.5(s, 1H), 8.3(s, 1H), 8.25(s, 1H), 7.9(s, 1H),7.55(m, 1H), 7.3-7.4(m, 5H), 5.2(s, 2H), 4.5(s, 2H), 4.0(s, 2H), 3.4(q,2H), 3.0(s, 6H), 1.3(t, 3H) 227 389 391 228 457.3 459.1 — 229 456.3458.1 — 230 433.3 435.1 — 231 487 489 (CD₃OD) 9.30(s, 2H), 9.04(d, 2H),8.89 (d, 1H), 8.11(d, 1H), 7.54(t, 1H), 4.46 (q, 2H), 4.02(m, 2H),3.59(m, 2H), 2.89 (m, 2H), 1.44(t, 2H), 1.13(t, 3H) ppm. 232 456.3 458.3(CD₃OD) 9.22(s, 1H), 9.05(d, 2H), 8.92 (s, 1H), 8.78(d, 1H), 8.17(s,1H), 8.08 (d, 1H), 7.54(dd, 1H), 4.42(s, 2H), 3., 52 (m, 4H), 3.39(q,4H), 3.28(m, 4H), 1.26 (t, 3H) 233 — 459.1 (CD₃OD) 9.22(s, 1H), 9.06(d,2H), 8.96 (s, 1H), 8.77(d, 1H), 8.22(s, 1H), 8.07 (d, 1H), 7.56(dd, 1H),4.49(q, 2H), 4.42 (s, 2H), 3., 52(m, 4H), 3.29(m, 4H), 1.45(t, 3H) 234537 (CD₃OD) 9.22(s, 1H), 9.04(d, 2H), 8.90 (s, 1H), 8.54(d, 1H), 8.16(s,1H), 7.99 (d, 1H), 7.54(dd, 1H), 4.78(s, 2H), 4.49 (q, 2H), 3.69 &3.63(m, 8H), 3.00(s, 3H), 1.45(t, 3H) 235 534.2 536.1 (CD₃OD) 9.20(s,1H), 9.02(d, 2H), 8.82 (s, 1H), 8.52(d, 1H), 8.09(s, 1H), 7.98 (d, 1H),7.52(dd, 1H), 4.78(s, 2H), 3.69 &3.62(m, 8H), 3.39(q, 2H), 3.00(s, 3H),1.25(t, 3H) 236 496.4 498.3 (CD₃OD) 9.28(s, 1H), 9.06(br s, 2H), 8.96(s,1H), 8.85(br s, 1H), 8.24(s, 1H), 8.15(br s, 1H), 7.56(br s, 1H), 4.49(q, 2H), 4.42(s, 2H), 3.73(br s, 4H), 3.35 (br s, 4H), 3.01(br s, 1H),1.45(t, 3H), 1.20(br s, 2H), 1.00(br s 2H) 237 496.4 498.3 (CDCl₃)11.82(br s, 1H), 8.88(s, 1H), 8.71(br s, 2H), 8.48(s, 1H), 7.89(d, 1H),7.79(s, 1H), 7.42(d, 1H), 7.05(br s, 1H), 3.71(s, 2H), 3.46(q, 2H), 2.70& 2.55(m, 8H), 1.28(t, 3H), 0.45-0.41(m, 4H) 238 447.2 449 12.35(s, 1H);9.07(d, 2H); 8.82(s, 1H); 8.41(d, 1H); 8.13(s, 1H); 7.95(d, 1H); 7.57(t,1H); 6.7-5.2(br. s, 4H); 4.38(s, 2H); 4.32(q, 2H); 3.92(br. d, 4H); 3.32(br. d, 4H); 1.33(t, 3H). 239 490.1 492.2 (CD₃OD) 9.21(s, 1H), 9.05(d,2H), 8.92 (s, 1H), 8.54(d, 1H), 8.17(s, 1H), 7.97 (d, 1H), 7.55(dd, 1H),4.78(s, 2H), 4.49 (q, 2H), 4.01(br dd, 2H), 3.74(br d, 2H), 3.43(br dd,2H), 3.27(br d, 2H), 1.45(t, 3H) 240 471.3 473 (CD₃OD) 9.28(s, 1H),9.05(br s, 2H), 8.96(s, 1H), 8.89(s, 1H), 8.25(s, 1H), 8.17(s, 1H),7.55(br s, 1H), 4.49(q, 2H), 4.39(s, 2H), 3.64-3.13(m, 8H), 3.00(s, 3H),1.45(t, 3H) 241 — 531.01 1.3(t, 3H), 1.55(d, 3H), 3.3(br s, 4H), 3.9(brs, 4H), 4.0(q, 1H), 4.35(q, 2H), 4.6(s, 2H), 7.6(dd, 1H), 7.8(d, 1H),8.0 (s, 1H), 8.4(d, 1H), 8.42(s, 1H), 8.7(s, 1H), 8.8(d, 1H), 9.15(s,1H), 11 . . . 2(br s, 1H) 242 486.2 488.1 (CD₃OD) 9.33(s, 2H), 8.92(d,1H), 8.79 (d, 1H), 8.47(m, 2H), 8.09(d, 1H), 7.84 (m, 1H), 4.42(q, 2H),4.05(m, 2H), 3.67 (m, 2H), 3.39(m, 2H, underneath solvent peak), 3.00(m,2H), 1.42(t, 3H), 1.28(d, 6H)ppm 243 488.2 490.05 1.3(t, 3H), 3.2(m,2H), 3.5(m, 2H), 3.7 (m, 2H), 3.9(m, 2H), 4.0(m, 2H), 4.3 (q, 2H),4.8(m, 2H), 7.6(7, 1H), 8.1(d, 1H), 8.2(br s, 1H), 8.6(d, 1H), 8.65(d,1H), 8.8(d, 1H), 9.05(d, 2H), 11.6(br s, 1H), 12.7(br s, 1H) 244 457.21459.09 1.35(t, 3H), 2.8(br s, 3H), 3.2(m, 2H), 3.4(m, 2H), 3.55(m, 2H),4.3(m, 2H), 4.35(q, 2H), 7.6(t, 1H), 8.1(d, 1H), 8.3 (br s, 1H), 8.55(d,1H), 8.6(d, 1H), 8.7 (d, 1H), 9.05(d, 2H), 11.2(br s, 1H), 12.4(br s,1H) 245 529.2 531.1 (CD₃OD) 9.08(d, 1H), 9.01(d, 2H), 8.82(d, 1H),8.30(d, 1H), 8.04(d, 1H), 7.68(d, 1H), 7.51(dd, 1H), 4.63(s, 2H),4.47(q, 2H), 4.22(s, 2H), 3.91(br s, 4H), 3.49(br s, 4H), 3.43(s, 3H),1.44(t, 3H) 246 555.3 557.1 (CD₃OD) 9.23(s, 1H), 9.04(d, 2H), 8.90 (s,1H), 8.56(d, 1H), 8.17(s, 1H), 8.00 (d, 1H), 7.55(dd, 1H), 4.77(s, 2H),4.49 (q, 2H), 4.12-3.84(m, 6H), 3.57(br s, 4H), 3.48(br s, 1H), 2.18(m,2H), 1.97 (m, 2H), 1.45(t, 3H) 247 485.1 487 (CD₃OD) 9.34(s, 2H),8.93(d, 1H), 8.80 (d, 1H), 8.48(m, 2H), 8.10(d, 1H), 7.85 (t, 1H),4.88(s, 2H), 4.44(q, 2H), 4.21 (s, 2H), 3.86(m, 2H), 3.79(m, 2H), 3.09(s, 3H), 1.42(t, 3H)ppm. 248 458.15 460.02 1.23(t, 3H) 3.17(m, 4H)3.65(m, 4H) 4.34(q, 2H) 4.77(s, 2H) 7.57(t, 1H) 8.11(s, 1H) 8.61(s, 1H)9.06(d, 2H) 9.39(s, 2H) 9.87(br s, 2H) 249 472.3 474 (CD₃OD) 9.17(s,1H), 9.04(d, 2H), 8.92 (s, 1H), 8.45(d, 1H), 8.15(s, 1H), 7.87 (d, 1H),7.55(dd, 1H), 4.68(s, 2H), 4.69 (q, 2H), 4.11(dd, 1H), 4.02-3.95(m, 2H),3.57(m, 2H), 3.03(dd, 1H), 1.44(t, 3H), 1.26(d, 3H) 250 499.2 501.3(CD₃OD) 9.25(s, 1H), 9.06(d, 2H), 8.97 (s, 1H), 8.84(d, 1H), 8.23(s,1H), 8.12 (d, 1H), 7.56(dd, 1H), 4.49(q, 2H), 4.37 (s, 2H), 3.65-3.12(m,9H), 1.46-1.43(m, 9H) 251 514.9 517 (CD₃OD) 9.27(s, 1H), 9.05(d, 2H),8.95 (s, 1H), 8.86(d, 1H), 8.25(s, 1H), 8.16 (d, 1H), 7.56(dd, 1H),4.49(q, 2H), 4.46 (s, 2H), 3.81-3.50(m, 12 H), 3.44(s, 3H), 1.45(t, 3H)252 527.2 529 (CD₃OD) 9.06(s, 1H), 8.97(d, 2H), 8.76 (s, 1H), 8.28(d,1H), 8.00(s, 1H), 7.69 (d, 1H), 7.49(dd, 1H), 4.65(s, 2H), 4.45 (q, 2H),3.99(br s, 4H), 3.49(br s, 4H), 2.99(hept, 1H), 1.44(t, 3H), 1.14(d, 6H)253 502 504 (CD₃OD) 9.08(d, 2H), 8.73(s, 1H), 8.51 (s, 1H), 8.38(dd,1H), 8.07(d, 1H), 7.92 (m, 1H), 7.77(d, 1H), 7.64(m, 1H), 4.67 (s, 2H),4.48(q, 2H), 4.01(s, 2H), 3.65 (m, 4H), 3.06(m, 2H), 1.43(t, 2H), 1.13(t, 3H)ppm. 254 454.17 456.02 14.52(s, 1H); 9.22(s, 2H); 9.05(d, 2H);8.56(d, 1H); 8.04(d, 1H); 7.74(s, 1H); 7.62(s, 1H); 7.55(t, 1H);6.8-5.6(br. s); 5.79(s, 2H); 4.33(q, 2H); 2.62(s, 3H); 1.33(t, 3H). 255530.17 532.03 1.1(d, 6H), 1.35(t, 3H), 2.3(s, 6H), 3.5 (m, 2H), 3.6(m,2H), 3.9(s, 2H), 4.3(q, 2H), 4.6(s, 2H), 4.65(m, 1H), 7.7(d, 1H), 7.9(s,1H), 8.0(dt, 1H), 8.3(s, 1H), 8.4(dd, 1H), 8.8(d, 1H), 8.85(m, 1H),9.1(s, 1H) 256 486.23 488.05 1.3(d, 6H), 1.35(t, 3H), 3.1(m, 2H), 3.5(m, 1H), 3.6(m, 4H), 4.3(q, 2H), 4.8 (m, 2H), 7.6(t, 1H), 7.9(s, 1H),8.5(s, 1H), 8.9(s, 2H), 9.05(d, 1H), 10.5(br s, 1H) 257 499.2 501.1(CD₃OD) 9.34(s, 2H), 8.93(m, 1H), 8.81(d, 1H), 8.49(m, 2H), 8.11(d, 1H),7.85(t, 1H), 4.87(s, 2H), 4.42(q, 2H), 4.11(br s, 2H), 3.87(br m, 4H),3.71(m, 3H), 1.48(d, 6H), 1.42(t, 3H) ppm. 258 571.3 573.1 (CDCl₃)12.75(br s, 1H), 12.29(s, 1H), 8.94(d, 2H), 8.92(s, 1H), 8.60(s, 1H),8.05(s, 1H), 8.04(d, 1H), 7.59(d, 1H), 7.25(dd, 1H), 4.46(q, 2H),4.23(br s, 1H), 3.86(d, 1H), 3.80(d, 1H), 3.65(d, 1H), 3.19(ddd, 1H),2.86(d, 1H), 2.66 (d, 1H) 259 — 473 (CD₃OD) 9.24(s, 1H), 9.04(d, 2H),8.94 (s, 1H), 8.81(d, 1H), 8.22(s, 1H), 8.11 (d, 1H), 7.55(dd, 1H),4.49(q, 2H), 4.42 (s, 2H), 3.77-2.89(m, 7H), 1.45(t, 3H), 1.41(d, 3H)260 485.3 487.3 (CD₃OD) 9.24(s, 1H), 9.06(d, 2H), 8.96 (s, 1H), 8.83(d,1H), 8.23(s, 1H), 8.11 (d, 1H), 7.56(dd, 1H), 4.49(q, 2H), 4.39 (s, 2H),3.76(m, 2H), 3.40(d, 2H), 2.80 (d, 2H), 1.45(t, 3H), 1.40(d, 6H) 261485.2 487 (CD₃OD) 9.23(s, 1H), 9.06(d, 2H), 8.97 (s, 1H), 8.82(d, 1H),8.24(s, 1H), 8.13 (d, 1H), 7.56(dd, 1H), 4.74(d, 2H), 4.49 (q, 2H),4.25(d, 1H), 3.80-2.92(m, 6H), 1.45(t, 3H), 1.36(d, 6H) 262 513.2 515(CD₃OD) 9.10(s, 1H), 9.02(d, 2H), 8.85 (s, 1H), 8.31(d, 1H), 8.06(s,1H), 7.68 (d, 1H), 7.52(dd, 1H), 4.62(s, 2H), 4.46 (q, 2H), 3.92-3.16(m,8 H), 2.48(q, 2H), 1.86(m, 2H), 1.44(t, 3H), 1.14(t, 3 H) 263 — 557.3(CD₃OD) 9.11(s, 1H), 9.03(d, 2H), 8.85 (s, 1H), 8.32(d, 1H), 8.07(s,1H), 7.69 (d, 1H), 7.52(dd, 1H), 4.63(s, 2H), 4.47 (q, 2H), 3.99-3.79(m,8 H), 3.50-3.45 (m, 5H), 2.15(m, 2H), 1.44(t, 3H) 264 — 501.1 (CD₃OD)9.10(s, 1H), 9.03(d, 2H), 8.85 (s, 1H), 8.62(d, 1H), 8.08(s, 1H), 7.94(d, 1H), 7.52(dd, 1H), 4.46(q, 2H), 4.12 (s, 2H), 3.46-3.01(m, 10H),1.80(m, 2H), 1.43(t, 3H), 1.04(t, 3H) 265 — 531.1 (CD₃OD) 9.21(s, 1H),8.96(d, 2H), 8.82 (s, 1H), 8.59(d, 1H), 8.12(s, 1H), 8.06 (d, 1H),7.48(dd, 1H), 4.75(s, 2H), 4.42 (q, 2H), 4.12(q, 2H), 3.83(br s, 4H),3.47(br s, 4H), 1.38(t, 3H), 1.23(t, 3H) 266 543.2 545 (CD₃OD) 9.33(s,1H), 8.99(d, 2H), 8.83 (s, 1H), 8.79(br s, 1H), 8.18(s, 1H), 7.54(br s,1H), 4.93(m, 1H), 4.89(s, 2H), 4.49(q, 2H), 3.90(br s, 4H), 3.57 (br s,4H), 1.45(t, 3H), 1.29(d, 6H) 267 516 518 — 268 557.3 559.2 (CD₃OD)9.08(s, 1H), 8.969(d, 2H), 8.78(s, 1H), 8.29(d, 1H), 8.01(s, 1H),7.67(d, 1H), 7.49(dd, 1H), 4.62(s, 2H), 4.45(q, 2H), 3.93(d, 2H),3.85(br s, 4H), 3.46(br s, 4H), 1.96(m, 1H), 1.43 (t, 3 H), 0.98(d, 6 H)269 553.3 555.1 (CD₃OD) 9.15(s, 1H), 9.05(d, 2H), 8.91 (s, 1H), 8.39(d,1H), 8.14(s, 1H), 7.79 (d, 1H), 7.55(dd, 1H), 4.71(q, 2H), 4.68 (s, 2H),4.49(q, 2H), 3.88(br s, 4H), 3.49(br s, 4H), 1.82(t, 3H), 1.44(t, 3 H)270 557.3 559.2 (CD₃OD) 9.11(s, 1H), 9.03(d, 2H), 8.84 (s, 1H), 8.31(d,1H), 8.05(s, 1H), 7.68 (d, 1H), 7.52(dd, 1H), 4.63(s, 2H), 4.46 (q, 2H),3.96(br s, 4H), 3.52(br s, 2H), 3.44(br s, 2H), 2.71(t, 2H), 2.65(t,2H), 1.43(t, 3H) 271 573.2 575.2 (CD₃OD) 9.12(s, 1H), 9.05(d, 2H), 8.86(s, 1H), 8.32(d, 1H), 8.07(s, 1H), 7.68 (d, 1H), 7.53(dd, 1H), 4.63(s,2H), 4.46 (q, 2H), 4.37(s, 2H), 4.21(s, 2H), 3.98 (br s, 4H), 3.52(br s,2H), 3.47(br s, 2H), 1.44(t, 3H) 272 500.23 502.05 1.21(m, 9H) 3.17(s,1H) 3.61(m, 8H) 4.32(q, 2H) 4.65(s, 2H) 7.56(t, 1H) 8.10(s, 1H) 8.58(s,1H) 9.07(d, 2H) 9.30(s, 2H) 273 476 478 9.29(s, 2H), 8.66(s, 1H),8.02(s, 1H), 7.95(m, 2H), 7.59(m, 1H), 4.76(s, 2H), 4.30(m, 2H),3.94-3.68(m, 4H), 3.50- 3.17(m, 4H), 1.30(t, 3H) 274 417.1 419 9.1(s,2H), 9.0(s, 2H), 8.4(s, 1H), 7.8(s, 1H), 7.5(t, 1H), 4.1-4.2(q, 2H),3.7(s, 2H), 2.3(s, 6H), 1.3(t, 3H). 275 466 468 — 276 445.1 447 1.33(t,3H) 2.06(m, 1H) 2.26(m, 1H) 3.88(m, 4H) 4.33(q, 2H) 5.85(m, 1H) 6.97(d,1H) 7.55(t, 1H) 7.91(s, 1H) 8.08(d, 1H) 8.52(m, 2H) 9.05(d, 2H) 12.44(brs, 1H) 277 475.1 477 1.3(t, 3H), 2.3(s, 6H), 3.35(m, 4H), 3.9 (m, 4H),4.3(q, 2H), 4.6(s, 2H), 7.7(d, 1H), 7.9(s, 1H), 8.0(dt, 1H), 8.3(s, 1H),8.35(dd, 1H), 8.75(d, 1H), 8.8(br s, 1H), 9.1(d, 1H), 10.4(br s, 1H) 278502.1 504 1.3(t, 3H), 3.2(s, 3H), 3.4(br s, 4H), 3.7 (br s, 4H), 3.8(brs, 2H), 4.3(q, 2H), 4.8 (br s, 2H), 7.55(t, 1H), 8.0(d, 1H), 8.5 (d,1H), 9.0(s, 2H), 9.05(d, 2H), 11.8 (br s, 1H), 12.6(br s, 1H) 279 525.2527 — 280 567.2 569 (CD₃OD) 9.11(s, 1H), 9.03(d, 2H), 8.83 (s, 1H),8.33(d, 1H), 8.06(s, 1H), 7.68 (d, 1H), 7.52(dd, 1H), 4.63(s, 2H), 4.46(q, 2H), 3.94(m, 4H), 3.59(q, 2H), 3.47 (m, 4H), 1.44(t, 3H) 281 458.15459.98 9.11(br. s, 2H); 9.09(s, 1H); 8.82(d, 1H); 8.78(br. s, 1H);8.64(d, 1H); 8.28 (s, 1H); 8.10(dd, 1H); 7.88(s, 1H); 7.52 (dd, 1H);5.38(m, 1H); 5.5-4.2(br. s, 4H); 4.32(q, 2H); 3.45(m, 1H); 3.37(m, 1H);3.12(m, 2H); 2.05(M, 1 282 514.2 516 10.05(m, 1H); 9.24(m, 1H); 9.15(d,2H); 8.82(d, 1H); 8.67(d, 1H); 8.31(s, 1H); 8.12(m, 1H); 7.90(s, 1H);7.53(m, 1H); 5.52(m, 1H); 4.32(q, 2H); 3.78(m, 1H); 3.55-2.88(m, 4H);2.12(m, 1H); 2.02(m, 1H); 1.88(m, 1H); 1.33(t 283 519.15 521.02 1.3(t,3H), 2.35(s, 12H), 2.8(s, 3H), .3.0-3.7(br s, 10H), 4.3(q, 2H), 4.7(brs, 2H), 7.6(m, 1H), 7.9(s, 1H), 7.95(m, 2H), 8.65(m, 1H), 9.0(s, 2H) 290487.1 489 — 291 — 490 — 292 482.1 484 — 293 483 484.9 — 294 460.11461.96 1.15(t, 3H), 2.3(s, 9H), 3.25(m, 2H), 3.5(m, 4H), 3.8(m, 4H),7.5(br s, 1H), 7.6(m, 1H), 7.95(m, 1H), 8.0(s, 1H), 8.1(m, 1H), 8.2(m,1H), 8.4(d, 1H), 8.6 (s, 1H), 8.7(d, 1H), 10.3(br s, 1H) 295 — — (CD₃OD)9.13(d, 1H), 9.05(d, 2H), 8.92(d, 1H), 8.37(m, 1H), 8.13(d, 1H),7.75(dt, 1H), 7.55(t, 1H), 4.70(s, 2H), 4.49(q, 2H), 3.62(m, 4H),2.47(m, 4H), 1.44(t, 3H) ppm

Example 27

[0217] Gyrase ATPase Assay

[0218] The ATP hydrolysis activity of DNA gyrase was measured bycoupling the production of DP through pyruvate kinase/lactatedehydrogenase to the oxidation of NADH. This method has been describedpreviously (Tamura and Gellert, 1990, J. Biol. Chem., 265, 21342).

[0219] ATPase assays are carried out at 30° C. in buffered solutionscontaining 100 mM TRIS ph 7.6, 1.5 mM MgCl₂, 150 mM KCl. The couplingsystem contains (final concentrations) 2.5 mM phosphoenol pyruvate, 200μM nicotinamide adenine dinucleotide (NADH), 1 mM DTT, 30 ug/ml pyruvatekinase, and 10 ug/ml lactate dehydrogenase. 40 nanomolar enzyme (374 kDaGyr A2B2 subunit from Staphylococcus aureus) and a DMSO solution of theinhibitor to a final concentration of 4% are added and the reactionmixture is allowed to incubate for 10 minutes at 30° C. The reaction isthen started by the addition of ATP to a final concentration of 0.9 mMand the rate of NADH disappearance at 340 nanometers is measured overthe course of 10 minutes. The K_(i) values determined from rate versusconcentration profiles.

[0220] Compounds of the present invention were found to inhibit gyrase.In certain embodiments, compounds of the present invention inhibitgyrase with a K_(i) value of less than 50 nM in the above assay.

Example 28

[0221] Topo IV ATPase AssaM:

[0222] The conversion of ATP to ADP by Topo4 enzyme is coupled to theconversion of NADH to NAD+ and measured by the change in absorbance at340 nm. Topo4 is incubated with inhibitor (4% DMSO final) in buffer for10 minutes at 30° C. Reaction is initiated with ATP and rates aremonitored continuously for 20 minutes at 30° C. on a Molecular DevicesSpectraMAX plate reader. The inhibition constant, Ki, is determined fromplots of rate vs. [Inhibitor] fit to the Morrison Equation for tightbinding inhibitors.

[0223]S. aureus Topo4 Buffer:

[0224] 100 mM Tris 7.5, 2 mM MgCl2, 200 mM K.Glutamate, 2.5 mMphosphoenol pyruvate, 0.2 mM NADH, 1 mM DTT, 4.25 μg/mL linearized DNA,50 μg/mL BSA, 30 μg/mL pyruvate kinase, and 10 μg/mL lactatedehyrodgenase (LDH).

[0225]E. coli Topo4 Buffer:

[0226] 100 mM Tris 7.5, 6 mM MgCl2, 20 mM KCl, 2.5 mM phosphoenolpyruvate, 0.2 mM NADH, 10 mM DTT, 5.25 μg/mL linearized DNA, 50 μg/mLBSA, 30 μg/mL pyruvate kinase, and 10 μg/mL lactate dehyrodgenase (LDH).

[0227] Compounds of the present invention were found to inhibit TopoIV.In certain embodiments, compounds of the present invention inhibitTopoIV with a K_(i) value of less than 50 nM in the above assay.

Example 29 Susceptibility Testing in Liquid Media

[0228] Compounds of this invention were also tested for antimicrobialactivity by susceptibility testing in liquid media. Such assays wereperformed within the guidelines of the latest NCCLS document governingsuch practices: “M7-A5 Methods for dilution Antimicrobial SusceptibilityTests for Bacteria that Grow Aerobically; Approved Standard—FifthEdition (2000)”. Other publications such as “Antibiotics in LaboratoryMedicine” (Edited by V. Lorian, Publishers Williams and Wilkins, 1996)provide essential practical techniques in laboratory antibiotic testing.Essentially, several discrete bacterial colonies of Staphylococcusaureus (3 to 7) from a freshly streaked plate were transferred to anappropriate rich broth medium such as MHB, supplemented whereappropriate for the more fastidious organisms. This was grown overnightto high density followed by a 1 or 2-thousand-fold dilution to give aninoculation density of between 5×10⁵ and 5×10⁶ CFU per mL.Alternatively, the freshly picked colonies can be incubated at 37° C.for about 4 to 8 hours until the culture equals or exceeds a turbidityof a 0.5 McFarland standard (approximately 1.5×10⁸ cells per mL) anddiluted to give the same CFU per mL as above. In a more convenientmethod, the inoculum was prepared using a commercially availablemechanical device (the BBL PROMPT System) that involves touching fivecolonies directly with a wand, containing crosshatch grooves at itsbottom, followed by suspension of the bacteria in an appropriate volumeof saline. Dilution to the appropriate inoculum cell density was madefrom this cell suspension. The broth used for testing consists of MHBsupplemented with 50 mg per L of Ca²⁺ and 25 mg per L of Mg²⁺. Standarddilution panels of control antibiotics were made and stored as in theNCCLS standard M7-A5, the dilution range typically being in the 128 μgper mL to 0.015 μg per mL (by 2-fold serial dilution). The testcompounds were dissolved and diluted fresh for experimentation on thesame day; the same or similar ranges of concentration as above beingused. The test compounds and controls were dispensed into a multiwellplate and test bacteria added such that the final inoculation wasapproximately 5×10⁴ CFU per well and the final volume was 100 μL. Theplates were incubated at 35° C. overnight (16 to 20 hours) and checkedby eye for turbidity or quantitated with a multiwell plate reader. Theendpoint minimal inhibitory concentration (MIC) is the lowestconcentration of drug at which the microorganism tested (Staphylococcusaureus) does not grow. Such determinations were also compared to theappropriate tables contained in the above two publications to ensurethat the range of antibacterial activity is within the acceptable rangefor this standardized assay.

[0229] Compounds of the present invention were found to haveantimicrobial activity in the above-described S. aureus MIC assay.

[0230] While we have described a number of embodiments of the presentinvention, it is apparent that our basic constructions may be altered toprovide other embodiments which utilize the products and processes ofthis invention.

We claim:
 1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: W is selectedfrom nitrogen, CH, or CF; X is selected from CH or CF; Z is O or NH; R¹is phenyl or a 5-6 membered heteroaryl ring having 1-3 heteroatomsindependently selected from oxygen, nitrogen, or sulfur, wherein: R¹ issubstituted with 0-3 groups independently selected from -(T)_(y)-Ar, R′,oxo, C(O)R′, CO₂R′, OR′, N(R′)₂, SR′, NO₂, halogen, CN, C(O)N(R′)₂,NR′C(O)R′, SO₂R′, SO₂N(R′)₂, or NR′SO₂R′; y is 0 or 1; T is a straightor branched C₁₋₄ alkylidene chain, wherein one methylene unit of T isoptionally replaced by —O—, —NH—, or —S—; each R′ is independentlyselected from hydrogen, C₁₋₄ aliphatic, or a 5-6 membered saturated,unsaturated, or aryl ring having 0-3 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, wherein: R′ is substituted with 0-3groups independently selected from halogen, oxo, R^(o), N(R^(o))₂,OR^(o), CO₂R^(o), NR^(o)C(O)R^(o), C(O)N(R^(o))₂, SO₂R^(o),SO₂N(R^(o))₂, or NR^(o)SO₂R^(o), wherein: each R^(o) is independentlyselected from hydrogen, C₁₋₄ aliphatic, or a 5-6 membered saturated,unsaturated, or aryl ring having 0-3 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, and wherein: two substituents onadjacent positions of R¹ may be taken together to form a 5-7 memberedsaturated, partially unsaturated, or aryl ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; Ar is a 3-8membered saturated, unsaturated, or aryl ring, a 3-7 memberedheterocyclic ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or a 5-6 membered heteroaryl ring having1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur,wherein: Ar is substituted with 0-3 groups independently selected fromR′, oxo, CO₂R′, OR′, N(R′)₂, SR′, NO₂, halogen, CN, C(O)N(R′)₂,NR′C(O)R′, SO₂R′, C(O)R′, SO₂N(R′)₂, or NR′SO₂R′; R² is selected fromhydrogen or a C₁₋₃ aliphatic group; and Ring A is a 5-6 memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, provided that said ring has a hydrogen-bondacceptor in the position adjacent to the point of attachment to Ring B,wherein: Ring A is substituted with 0-3 groups independently selectedfrom R′, oxo, CO₂R′, OR′, N(R′)₂, SR′, NO₂, halogen, CN, C(O)N(R′)₂,NR′C(O)R′, SO₂R′, SO₂N(R′)₂, or NR′SO₂R′, and wherein: two substituentson adjacent positions of Ring A may be taken together to form a 5-7membered saturated, partially unsaturated, or aryl ring having 0-3heteroatoms independently selected from nitrogen, oxygen, or sulfur. 2.The compound according to claim 1, wherein Ring A is selected from thefollowing optionally substituted rings:


3. The compound according to claim 2, wherein Ring A is an optionallysubstituted ring selected from rings a, f, l, s, w, y, or z:


4. The compound according to claim 1, wherein: R¹ is selected from anoptionally substituted phenyl or 5-6 membered heteroaryl ring having 1-2nitrogens.
 5. The compound according to claim 4, wherein R¹ is anoptionally substituted ring selected from pyrid-2-yl, pyrid-3-yl,pyrid-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl,pyrimidin-6-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, orimidazol-5-yl.
 6. The compound according to claim 5, wherein R¹ issubstituted with 0-2 groups independently selected from halogen, oxo,R′, CO₂R′, OR′, N(R′)₂, SR′, C(O)N(R′)₂, NR′C(O)R′, SO₂R′, SO₂N(R′)₂, orNR′SO₂R′.
 7. The compound according to claim 6, wherein R² is selectedfrom methyl, ethyl, isopropyl, or cyclopropyl.
 8. The compound accordingto claim 1, wherein said compound is of formula II-a:

or a pharmaceutically acceptable salt thereof.
 9. The compound accordingto claim 1, wherein said compound is of formula III:

or a pharmaceutically acceptable salt thereof, wherein: the pyridonering depicted is substituted with 0-2 groups independently selected fromhalogen, oxo, R′, CO₂R′, OR′, N(R′)₂, SR′, C(O)N(R′)₂, NR′C(O)R′, SO₂R′,SO₂N(R′)₂, or NR′SO₂R′.
 10. The compound according to claim 9, whereinsaid compound is of formula III-a:

or a pharmaceutically acceptable salt thereof.
 11. The compoundaccording to claim 10, wherein: R′ is hydrogen or C₁₋₄ aliphatic, andwherein: R′ is optionally substituted with phenyl or pyridyl.
 12. Thecompound according to claim 1, wherein said compound is of formula IV:

or a pharmaceutically acceptable salt thereof.
 13. The compoundaccording to claim 12, wherein Ar is an optionally substituted 5-6membered saturated ring having 1-2 heteroatoms independently selectedfrom oxygen, nitrogen, or sulfur.
 14. The compound according to claim12, wherein Ar is an optionally substituted 5-membered heteroaryl ringhaving 1-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur.
 15. The compound according to claim 12, wherein Ar is anoptionally substituted 6-membered heteroaryl ring having 1-3 nitrogens.16. The compound according to claim 12, wherein Ar is optionallysubstituted phenyl.
 17. The compound according to claim 1, wherein saidcompound is of formula V:

or a pharmaceutically acceptable salt thereof.
 18. The compoundaccording to claim 17, wherein said compound is of formula VI:

or a pharmaceutically acceptable salt thereof.
 19. The compoundaccording to any one of claims 8, 11, 12, or 17 wherein R² is ethyl. 20.A compound selected from the group consisting of:


21. A composition comprising a compound according to claim 1, and apharmaceutically acceptable carrier, adjuvant, or vehicle.
 22. Thecomposition according to claim 21, additionally comprising an additionaltherapeutic agent selected from an antibiotic, an anti-inflammatoryagent, a matrix metalloprotease inhibitor, a lipoxygenase inhibitor, acytokine antagonist, an immunosuppressant, an anti-cancer agent, ananti-viral agent, a cytokine, a growth factor, an immunomodulator, aprostaglandin an anti-vascular hyperproliferation compound, or an agentwhich increases the susceptibility of bacterial organisms toantibiotics.
 23. A method of inhibiting gyrase activity in a biologicalsample or in a patient, comprising the step of contacting saidbiological sample with: a) a composition according to claim 21; or b) acompound according to claim
 1. 24. A method of inhibiting TopoIVactivity in a biological sample or in a patient, comprising the step ofcontacting said biological sample with: a) a composition according toclaim 21; or b) a compound according to claim
 1. 25. A method ofinhibiting gyrase and TopoIV activity in a biological sample or in apatient, comprising the step of contacting said biological sample with:a) a composition according to claim 21; or b) a compound according toclaim
 1. 26. A method of decreasing bacterial quantity in a patient,comprising the step of administering to said patient: a) a compositionaccording to claim 21; or b) a compound according to claim
 1. 27. Amethod of treating, preventing, or lessening the severity of, abacterial infection in a patient, comprising the step of administeringto said patient: a) a composition according to claim 21; or b) acompound according to claim
 1. 28. The method according to claim 27,wherein the bacterial infection to be treated is characterized by thepresence of one or more of the following: Streptococcus pneumoniae,Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium,Klebsiella pneumoniae, Enterobacter sps. Proteus sps. Pseudomonasaeruginosa, E. coli, Serratia marcesens, Staphylococcus aureus, Coag.Neg. Staph, Haemophilus influenzae, Bacillus anthracis, Mycoplasmapneumoniae, Moraxella catarralis, Chlamydia pneumoniae, Legionellapneumophila, Staphylococcus epidermidis, Mycobacterium tuberculosis, orHelcoibacter pylori.
 29. The method according to claim 28, wherein thebacterial infection to be treated is selected from one or more of thefollowing: a urinary tract infection, a respiratory infection,pneumonia, prostatitis, a skin or soft tissue infection, anintra-abdominal infection, a blood stream infection, or an infection offebrile neutropenic patients.
 30. The method according to claim 29,further comprising the step of administering to said patient anadditional therapeutic agent either as part of a multiple dosage formtogether with said compound or as a separate dosage form.
 31. The methodaccording to claim 28, further comprising the step of administering tosaid patient an agent that increases the susceptibility of bacterialorganisms to antibiotics.